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

• ClinicalTrials.gov Identifier: NCT03750552
• Recruitment Status: Completed
• First Posted: November 23, 2018
• Results First Posted: September 14, 2022
• Last Update Posted: September 14, 2022
• Sponsor: Theravance Biopharma
• Information provided by (Responsible Party): Theravance Biopharma

Tracking Information

• First Submitted Date: November 20, 2018
• First Posted Date: November 23, 2018
• Results First Submitted Date: July 20, 2022
• Results First Posted Date: September 14, 2022
• Last Update Posted Date: September 14, 2022
• Actual Study Start Date: January 24, 2019
• Actual Primary Completion Date: July 21, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 20, 2022)

Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 20, 2018)

Change from baseline in OHSA#1 at Week 4 [ Time Frame: Baseline to Week 4 ]

Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA ). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout.

Current Secondary Outcome Measures (submitted: July 20, 2022)

• Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to Week 4 ]

Original Secondary Outcome Measures (submitted: November 20, 2018)

• Change from baseline in OHSA composite score in Weeks 1 to 4 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4 ]
  Orthostatic Hypotension Symptom Assessment (OHSA ) is an assessment of the severity of symptoms from low blood pressure.
• Change from baseline in OHDAS composite score in Weeks 1 to 4 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4 ]
  Orthostatic Hypotension Daily Activities Scale (OHDAS ) is an assessment of how low blood pressure symptoms affect daily life.
• PGI-C at Week 4 [ Time Frame: Week 4 ]
  Using the Patient Global Impression of Change (PGI-C) scale, a subject rates their total improvement compared to baseline.
• Incidence of falls [ Time Frame: Week 4 ]
  Incidence of patient-reported falls.
• Standing systolic blood pressure during orthostatic standing test [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4 ]
  Systolic blood pressure taken during the standing portion of the orthostatic standing test.
• Change from baseline in UPDRS at Week 4 [ Time Frame: Baseline to Week 4 ]
  Unified Parkinson's Disease Rating Scale (UPDRS) is a clinical rating scale for Parkinson's Disease (PD). Outcome measure only applies to subjects with PD.
• Change from baseline in PDQ-8 at Week 4 [ Time Frame: Baseline to Week 4 ]
  Parkinson's Disease Questionnaire-8 (PDQ-8) is an assessment for Parkinson's Disease (PD) subjects. Outcome measure only applies to subjects with PD.
• Change from baseline in COMPASS-31 at Week 4 [ Time Frame: Baseline to Week 4 ]
  Composite Autonomic Symptoms Score-31 (COMPASS-31) is an assessment that provides a quantitative measure of autonomic symptoms. Outcome measure only applies to subjects with Multiple System Atrophy (MSA).
• Change from baseline in UMSARS at Week 4 [ Time Frame: Baseline to Week 4 ]
  Unified Multiple System Atrophy Rating Scale (UMSARS) is an assessment for Multiple System Atrophy (MSA) subjects. Outcome measure only applies to subjects with MSA.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clinical Effect of Ampreloxetine (TD-9855) for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
• Official Title: A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure
• 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).
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Parallel assignment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Symptomatic Neurogenic Orthostatic Hypotension

Intervention

• Drug: ampreloxetine
  Oral tablet, QD
  Other Name: TD-9855
• Drug: Placebo
  Oral tablet, QD

Study Arms

• Experimental: ampreloxetine
  Participants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks.
  Intervention: Drug: ampreloxetine
• Placebo Comparator: Placebo
  Participants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 13, 2021): 195
• Original Estimated Enrollment (submitted: November 20, 2018): 188
• Actual Study Completion Date: July 21, 2021
• Actual Primary Completion Date: July 21, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Bulgaria, Canada, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Russian Federation, Spain, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03750552
• Other Study ID Numbers: 0169; 2018-003289-15 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

• Current Responsible Party: Theravance Biopharma
• Original Responsible Party: Same as current
• Current Study Sponsor: Theravance Biopharma
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Monitor; Theravance Biopharma

• PRS Account: Theravance Biopharma
• Verification Date: August 2022