Clinical Effect of Ampreloxetine (TD-9855) for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure

A Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH. The study consists of 3 periods: (i) 4-week screening, (ii) 4-week randomized treatment, and (iii) 2-week follow up. The trial utilizes an operational design featuring the ability to conduct protocol required visits as either in clinic or remote visits (except Screening visit).

• ampreloxetine (Drug), also known as TD-9855: Oral tablet, QD
• Placebo (Drug): Oral tablet, QD

Primary outcomes

• Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4 [Baseline and Week 4]: OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale where each question uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout. A mean negative change from baseline indicates a better outcome.

Secondary outcomes

• Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4 [Baseline and Week 4]: OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale in which the composite score uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A mean negative change from baseline indicates a better outcome.
• Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4 [Baseline and Week 4]: OHDAS is an assessment of how low blood pressure symptoms affect daily life. OHDAS is a 4 item assessment in which the composite score uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A mean negative change from baseline indicates a better outcome.
• Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4 [Baseline and Week 4]: PGI-C was assessed using a 5-point scale where participants were asked to compare their current condition to their condition at baseline from 1 to 5, with 1 indicating the condition is very much improved and 5 indicating the condition is very much worse. These scores were analyzed in 2 categories: better and no change/worse.
• Number of Participants Who Experienced at Least One Fall [Up to Week 4]

Sex: All, ages: 30 Years to any

Inclusion Criteria:

* Subject is male or female and at least 30 years old.
* Subject must meet the diagnostic criteria of symptomatic nOH, as demonstrated by a sustained reduction in BP of ≥20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 minutes of being tilted-up to ≥60o from a supine position as determined by a tilt-table test.
* Subject must score at least a 4 on the Orthostatic Hypotension Symptom Assessment Question #1 at randomization visit.
* For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria (1992).
* For subjects with MSA only: Subject 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).
* For subjects with PAF only: Subject has documented impaired autonomic reflexes, including the Valsalva maneuver performed within 24 months from the date of randomization.
* Subject has plasma NE levels >100 pg/mL after being in seated position for 30 minutes.

Exclusion Criteria:

* Subject has a known systemic illness known to produce autonomic neuropathy, including but not limited to amyloidosis, and autoimmune neuropathies.
* Subject has a known intolerance to other NRIs or SNRIs.
* Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension unrelated to autonomic dysfunction.
* Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to randomization or requires concomitant use until the follow-up visit.
* Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to V1.

  * Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1.
* Subject has a known or suspected alcohol or substance abuse within the past 12 months (DSM-IV-TR® definition of alcohol or substance abuse).
* Subject has a clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months.
* Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to randomization.
* Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
* Subject has any significant uncontrolled cardiac arrhythmia.
* Subject has a Montreal Cognitive Assessment (MoCA) ≤23.
* Subject had a myocardial infarction in the past 6 months or has current unstable angina.
* Subject has known congestive heart failure (New York Heart Association \[NYHA\] Class 3 or 4).
* Subject has a clinically significant abnormal laboratory findings (e.g., alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] >3.0 x upper limit of normal \[ULN\]; blood bilirubin \[total\] >1.5 x ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2, or any abnormal laboratory value that could interfere with safety of the subject).
* Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Columbia Suicide Severity Rating Scale) (Baseline/Screening Version) subject should be assessed by the rater for risk of suicide and the subject's appropriateness for inclusion in the study.

Participant flow

Outcome results

• Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4 (Primary), Least squares mean, score on a scale: Ampreloxetine -1.69 +/- 0.290; Placebo -1.45 +/- 0.293 (p 0.574)
• Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4 (Secondary), Least squares mean, score on a scale: Ampreloxetine -1.32 +/- 0.200; Placebo -1.05 +/- 0.202 (p 0.331)
• Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4 (Secondary), Least squares mean, score on a scale: Ampreloxetine -1.22 +/- 0.265; Placebo -0.95 +/- 0.267 (p 0.481)
• Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4 (Secondary), Count of participants, Participants: Ampreloxetine 49; Placebo 45 (p 0.740)
• Number of Participants Who Experienced at Least One Fall (Secondary), Count of participants, Participants: Ampreloxetine 33; Placebo 22 (p 0.0903)

Adverse events

Time frame: Up to Day 43

Serious adverse events by term

Other adverse events by term

40 more terms not shown.

25 more sites not listed.

• Results publication: Freeman R, Kaufmann H, Biaggioni I, Iodice V, Jordan J, Vickery R, Geurin T, Kmiecik MJ, Norcliffe-Kaufmann L. Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial. Neurology. 2026 Aug 11;107(3):e218284. doi: 10.1212/WNL.0000000000218284. Epub 2026 Jul 20. PMID 42475649

• Study Protocol (PDF, 2020-08-05)
• Statistical Analysis Plan (PDF, 2021-07-19)

• Medical Monitor, Study director, Theravance Biopharma

NIH grants: 2018