Amendment 1 included the following changes: • Extended study from 26 weeks to 182 weeks • Added assigned EudraCT number • Added new Clinical Study Director • Increased the number of countries from 20 to 25 • Changed visit designation from days to weeks for ease of reference • Removed the requirement to discuss discontinuation of participants with the Sponsor’s medical monitor to comply with ethics committee standards • Added clarification of the variable assessments in the first 26 weeks vs. the remaining 158 weeks • Made the wording concise in exclusion criteria • Added allowance for participants to be concurrently enrolled in observational studies • Deleted language that was not relevant to this study (there were no “predose” requirements; all participants rolled over from previous study) • Added table for study extension visits • Updated to provide clarification of the variable assessments in the first 26 weeks vs. the remaining 158 weeks • Provided rationale for extending the study for an additional 3 years • Changed language for “Exploratory Endpoint” • Clarified this was an open-label (OL) study and participants were not “randomized” • Updated to provide clarification of what assessments were done if a participant terminated the study prior to Week 26 • Added the 3-year extension and detailed what assessments were done at visits after Visit 6 • Provided clarification regarding cannabinoid usage to comply with regulations in countries/states where cannabinoid use was not legal • Changed “1 month” to “30 days” for consistency with previous studies within the program.

Amendment 2, included the following non-administrative changes: • Added study and drug name and name of the new Clinical Study Director; references to “snOH” were changed to “symptomatic nOH” to clearly define disease under study and consistency throughout the document • Study design updated for the implementation of the Decentralized Platform in response to the COVID-19 pandemic • Clarification and elaboration that the number of participants in this study was based upon the number of participants completing Study 0170, and the anticipated incidence of syncopal and hypertensive events driven by this enrollment number • Re-ordered procedures for consistency with other ampreloxetine protocols 0169 and 0170 • Study 0145 was completed, and the results were presented in the protocol; clarified with more recent information regarding study status • Clarified where study visits could be conducted along with the inclusion of unscheduled visits • Introduced the Study Reference Manual as source • Additional instructions provided regarding the conduct of remote and in-clinic study visits and where reader could find additional details • Provided clarity on the optimal time(s) protocol procedures should be conducted • Removed statement regarding timing of ECG • Added information and instructions regarding the Unscheduled Visit • Maintaining a constant smoking habit was not required • Clarified that participants would be discontinued from the study in addition to stopping study medication if a stopping criterion was met • Contact information for medical monitoring was updated for coverage of Latin America sites • This was a safety study, and no efficacy data were analyzed • Introduction of statistical group providing support for IDMC • Updated principal investigator responsibility to include oversight of home health provider working with the site • Added additional information regarding electronic clinical outcome assessment data collection.