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

Phase 3
Completed
Conditions
Symptomatic Neurogenic Orthostatic Hypotension
Interventions
Drug: Placebo
Registration Number
NCT03750552
Lead Sponsor
Theravance Biopharma
Brief 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.

Detailed Description

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).

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
195
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.

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
PlaceboPlaceboParticipants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks.
ampreloxetineampreloxetineParticipants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks.
Primary Outcome Measures
NameTimeMethod
Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4Baseline 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 Outcome Measures
NameTimeMethod
Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4Baseline 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 4Baseline 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 4Baseline 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 FallUp to Week 4

Trial Locations

Locations (124)

Banner Sun Health Research Institute

🇺🇸

Sun City, Arizona, United States

Collaborative Neuroscience Network, LLC

🇺🇸

Long Beach, California, United States

Stanford Neuroscience Health Center

🇺🇸

Palo Alto, California, United States

Colorado Springs Neurological Associates, PC

🇺🇸

Colorado Springs, Colorado, United States

University of Colorado Health

🇺🇸

Loveland, Colorado, United States

Georgetown University Hospital, Dept. of Neurology

🇺🇸

Washington, District of Columbia, United States

Parkinson's Disease and Movement Disorders Center

🇺🇸

Boca Raton, Florida, United States

SFM Clinical Research

🇺🇸

Boca Raton, Florida, United States

Fixel Institute for Neurological Diseases

🇺🇸

Gainesville, Florida, United States

Neurostudies, Inc

🇺🇸

Port Charlotte, Florida, United States

Scroll for more (114 remaining)
Banner Sun Health Research Institute
🇺🇸Sun City, Arizona, United States

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