Clinical Effect of Ampreloxetine (TD-9855) for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
Condition: Symptomatic Neurogenic Orthostatic Hypotension
MeSH terms: Hypotension, Orthostatic; Pure Autonomic Failure; Hypotension
Intervention: ampreloxetine; Placebo
Intervention description: Oral tablet, QD; Oral tablet, QD
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 195.0
Sex: All
Minimum age: 30 Years
Healthy volunteers: No
Keywords: Symptomatic Neurogenic Orthostatic Hypotension; symptomatic nOH; multiple system atrophy; MSA; Parkinson's disease; PD; pure autonomic failure; PAF; primary autonomic failure; SEQUOIA; ampreloxetine; low blood pressure; dizziness; fainting; blacking out; lightheadedness; norepinephrine; hypotension; Parkinsonism; TD-9855; Neurogenic Orthostatic Hypotension; nOH; 0145; 145; 169; 0169; TD9855

Summary:

      A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in
      subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH with up to 4
      weeks of treatment.
    

Eligibility criteria:

        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.