Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
Condition: Symptomatic Neurogenic Orthostatic Hypotension; MSA; Parkinson's Disease (PD); Pure Autonomic Failure (PAF)
MeSH terms: Parkinson Disease; Hypotension, Orthostatic; Pure Autonomic Failure; Hypotension
Intervention: ampreloxetine; Placebo
Intervention description: Oral tablet, QD (Daily); Oral tablet, QD
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Open Label Extension followed by Randomized Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 203.0
Sex: All
Minimum age: 30 Years
Healthy volunteers: No
Keywords: Symptomatic Neurogenic Orthostatic Hypotension; symptomatic nOH; multiple symptom atrophy; MSA; Parkinson's disease; PD; pure autonomic failure; PAF; orthostatic hypotension; OH; REDWOOD; ampreloxetine; low blood pressure; dizziness; fainting; blacking out; lightheadedness; norepinephrine; hypotension; Neurogenic Orthostatic Hypotension; nOH; 170; 0170; 145; 0145; TD-9855; TD9855; Parkinsonism

Summary:

      A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating
      Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure
    

Eligibility criteria:

        Inclusion Criteria (For 0169 Completers Group):

          -  Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the
             opinion of the Investigator, could benefit from continued treatment with
             ampreloxetine. Only subjects with OHSA#1 score of ≤7 will be eligible for
             randomization for the double-blind treatment period.

          -  Subject has a minimum of 80% study medication compliance in Study 0169.

        Inclusion Criteria (For De Novo Group):

          -  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
             min of being tilted-up ≥60o from a supine position as determined by a tilt-table test.

          -  Subject must score at least a 4 on the OHSA#1 at V1.

          -  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 Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated
             position for 30 minutes.

        Exclusion Criteria (For 0169 Completers Group):

          -  Subject has a medical, laboratory, or surgical issue(s) deemed by the investigator to
             be clinically significant.

          -  Subject has an uncooperative attitude or reasonable likelihood of non-compliance with
             the protocol.

          -  Subject has a concurrent disease or condition that, in the opinion of the
             investigator, would confound or interfere with study participation or evaluation of
             safety, tolerability, or pharmacokinetics of the study drug.

        Exclusion Criteria (For De Novo Group):

          -  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 serotonin norepinephrine reuptake
             inhibitors (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 V1 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 known or suspected alcohol or substance abuse within the past 12 months
             (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
             [DSM-IV-TR®] definition of alcohol or substance abuse).

          -  Subject has a clinically unstable coronary artery disease, or has had a major
             cardiovascular or neurological event in the past 6 months.

          -  Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.

          -  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 is unable or unwilling to complete all protocol specified procedures including
             questionnaires.

          -  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 finding (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/1.73 m2, 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 Columbia Suicide Severity Rating Scale
             (C-SSRS)(Baseline/Screening Version). Subject should be assessed by the rater for risk
             of suicide and the subject's appropriateness for inclusion in the study.