Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic NOH in Participants with Multiple System Atrophy

Inclusion Criteria:

• Participant is male or female and at least 30 years old.

• Participant has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).

• Participant has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) confirmed by the Enrollment Steering Committee (ESC).

• Participant must meet the diagnostic criteria of nOH, as demonstrated by a sustainedreduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) within 3 min ofstanding as part of orthostatic standing test or being tilted up ≥60o from a supineposition as determined by a tilt-table test.

• Participant must score ≤4 on UMSARS Part IV at Visit 1 (Screening).

• Participant must score at least a 4 on the OHSA item 1 at Visit 2 (Day 1).

• Participant must be willing to not take any prohibited medications during the study.

• If participant is female, the participant must not be pregnant, breastfeeding, orplanning a pregnancy during the course of the study. A woman of childbearingpotential must have a documented negative pregnancy test at screening.

• During the study and for 30 days after receiving the last dose of the study drug,females of childbearing potential or males capable of fathering children must agreeto use highly effective birth control measures (failure rate <1% when usedconsistently and correctly) or agree to abstain from sexual intercourse.

• Participant is willing and able to provide signed and dated written informed consentto -participate prior to initiation of any study related procedures.

Participant is able to communicate well with the Investigator and clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.

Exclusion Criteria:

• Participant has a systemic illness known to produce autonomic neuropathy, including,but not limited to, amyloidosis and autoimmune neuropathies. Participant withdiabetes mellitus (DM) will be evaluated on a case-by-case basis by the medicalmonitor and considered ineligible unless they meet all of the following criteria:

• Well controlled type-2 DM in treatment with only oral medications and diet

• HbA1C of ≤7.5% performed during screening or up to 12 weeks before screening

• No clinically evident peripheral neuropathy (e.g., normal sensory examinationon peripheral extremities)

• No known retinopathy (e.g., annual ophthalmic exam is sufficient)

• No nephropathy (e.g., absence of albuminuria and GFR >60).

• Participant has a known intolerance to other NRIs or SNRIs.

• Participant currently uses concomitant antihypertensive medication for the treatmentof essential hypertension.

• Participant has used strong CYP1A2 inhibitors or inducers within 7 days or 5 halflives, whichever is longer, prior to Visit 2 (Day 1) or requires concomitant useuntil the Safety follow-up Visit.

• Participant has changed dose, frequency, or type of prescribed medication fororthostatic hypotension within 7 days prior to Visit 2 (Day 1).

• Midodrine and droxidopa (if applicable) must be tapered off and stopped at least 7days prior to Visit 2 (Day 1).

• Participant has known or suspected alcohol or substance abuse within the past 12months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, TextRevision [DSM IV TR®] definition of alcohol or substance abuse).

• Participant has clinically unstable coronary artery disease or had a majorcardiovascular event (e.g., myocardial infarction) in the past 6 months.

• Participant has significant uncontrolled cardiac arrhythmia, history of completeheart block, or significant QTc prolongation (≥450 msec for males and ≥470 msec forfemales).

• Participant has a new onset of a neurological event (i.e., seizures, confusion,altered levels of consciousness, etc.) in the past 6 months.

• Participant has used any monoamine oxidase inhibitor (MAOI) within 14 days prior toVisit 2 (Day 1).

• Participant has a history of untreated closed angle glaucoma, or treated closedangle glaucoma that, in the opinion of an ophthalmologist, might result in anincreased risk to the participant.

• Participant has a Montreal Cognitive Assessment (MoCA) <21.

• Participant is unable or unwilling to complete all protocol specified proceduresincluding questionnaires.

• Participant has known congestive heart failure (New York Heart Association [NYHA]Class 3 or 4).

• Participant has had any malignant disease, other than carcinoma in situ of thecervix or basal cell carcinoma, within the past 2 years prior to Screening.

• Participant has a known gastrointestinal (GI) condition, which in the Investigator'sjudgment, may affect the absorption of study medication (e.g., ulcerative colitis,gastric bypass).

• Participant has psychiatric, neurological, or behavioral disorders that mayinterfere with the cognitive ability of the participant to give informed consent,understand and comply with study procedures, or interfere with the conduct of thestudy.

• Participant is currently receiving any investigational drug or has received aninvestigational drug within 30 days of dosing. An investigational drug is defined asa drug that is not approved by a regulatory agency (e.g., Food and DrugAdministration [FDA]).

• Participant has a clinically significant abnormal laboratory finding(s) (e.g.,alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥3.0 x upperlimit of normal [ULN]; blood bilirubin [total] ≥3.0 x ULN; estimated glomerularfiltration rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value thatcould interfere with safety of the participant).

• Participant has demonstrated lifetime suicidal ideation and/or suicidal behavior, asoutlined by the C-SSRS (Baseline/Screening Version). Participant should be assessedby the rater for risk of suicide and the participant's appropriateness for inclusionin the study.

• Participant has a concurrent disease or condition (e.g., COVID-19), or recentsurgery, that in the opinion of the Investigator, would confound or interfere withstudy participation or evaluation of safety, tolerability, or absorption of thestudy drug.

• Participant has known hypersensitivity to ampreloxetine (ampreloxetinehydrochloride), or any excipients in the formulation.

• Major surgery (i.e., procedures involving higher risk for infection and extendedrecovery period, such as, joint replacement, gastric bypass, open heart surgery,organ transplant, etc.) occurring less than 4 weeks prior to enrollment.