• Added the new drug name • Updated the number of countries • Increased the screening window to allow adequate time for NE sample processing • Updated the number of days in the screening period from 14 days (2 weeks) to 21 days (3 weeks) to allow adequate time for norepinephrine (NE) sample processing • Clarified and defined “sustained” in regard to systolic blood pressure (SBP) for at least 4 hours after 3 minutes of standing or after 5 minutes in the sitting position • Added ‘becoming pregnant’ as one of the stopping rules • Included a detailed description of highly acceptable methods of contraception including definition of sexual abstinence • Correction made in regard to diagnostic criteria • Made the wording concise in exclusion criteria • Removed specific OH medications • Removed the requirement that study medication must be taken “prior to breakfast” • Removed the requirement to contact the Sponsor prior to unblinding a participant's treatment • Clarified and defined acceptable contraception methods • Limited potential weight variations due to external factors like type of clothing etc. • Allowed fludrocortisone and cannabinoids • Prohibited the use of NE reuptake inhibitor (NRIs), NSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and psychostimulants • Updated the PGI-S to a 5-category scale • Removed reference to specific device (Kinesia 360) • Made language around assessments more generic • Allowed for possibility that some countries could not import the device

• Added study name • Changed personnel • Added additional sites and countries • Provided clarification that, apart from primary and key secondary objectives, other objectives were now classified explicitly as exploratory • Increased screening period to allow sufficient time for conduct of screening procedures • Removed requirement of discussion with Sponsor’s medical monitor • Extended screening window to 4 weeks, other corresponding changes • Clarified diagnosis of PAF • Allowed enrollment of participant's with controlled diabetes mellitus • Droxidopa was not available in all countries where the trial was conducted; thus, only if applicable • Excluded participants with hypersensitivity to ampreloxetine • Added continuation criteria to synopsis • Prohibited alpha blockers • Clarified efficacy endpoints • Clarified the statistical testing procedure as discussed in detail in statistical analysis plan (SAP) • Improved wording • Provided clearer instructions on conduct of corresponding study procedures • Added terms for completeness • Clarified Study 0145 was completed and results were presented in protocol • Clarified the optimal time(s) protocol procedures should conducted • Allowed for a confirmation if there was doubt per Investigator’s opinion • Clarification procedure conduct • Clarified the need for additional testing if the participant had diabetes mellitus • Provide clarification of the chemistry panel • Removed involvement of Sponsor should the Investigator decide to withdraw a participant from the study

• Additional electrocardiogram (ECG) added as a safety measure • Provided clarification on ECG completion duration • Clarified language and updated text to reflect internal standards

• Added study and drug name and name of the new Clinical Study Director • References to “snOH” changed to “symptomatic nOH” to clearly define disease under study and consistency throughout the document • Clarified references for consistency throughout the document to differentiate those that had signed study informed consent form • Clarified that Study 0145 was completed and results were presented in the protocol • Stated reasoning for update in study design, which was the implementation of the Decentralized Platform in response to the COVID-19 pandemic • Clarified the screening visit must be performed in clinic • Clarified the role of the Engineering Steering Committee and their decision-making process • Added exclusion for SARS-CoV-2 infection due to COVID-19 pandemic • Clarity added, and order revised for consistency across the document, and to reflect the removal of smoking status subgroups in the SAP • Added baseline NE subgroups • Changed the postbaseline blood sample collection time point for pharmacodynamic markers (NR and dihydroxyphenylglycol) from Day 29 to Day 57 • To the planned analyses of standing SBP at 3 minutes and at 10 minutes during the orthostatic standing test, addition of similar analyses of standing heart rate at 3 minutes and at 10 minutes.