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

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

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.

Study Overview

• Status: Completed
• Conditions: Symptomatic Neurogenic Orthostatic Hypotension
• Intervention / Treatment: Drug: ampreloxetine; Drug: Placebo

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
• Enrollment (Actual): 195
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Nedlands, Australia, 6009
    • Perron Institute for Neurological and Translational Science, QEII Medical Centre
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women'S Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health - Clinical Trials Centre
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universitat Innsbruck Abteilung Fur Neurologie
  • Tulln, Austria, 3430
    • Universitatsklinikum Tulln
  • Wien, Austria, 1160
    • Wilhelminenspital Wien Abteilung fur Neurologie
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • UMHAT Sveti Georgi EAD Clinic of Neurological Diseases
  • Sofia, Bulgaria, 1113
    • MHATNP Sv.Naum, EAD
  • Sofia, Bulgaria, 1431
    • UMHAT Alexandrovska EAD Clinic of Neurological Diseases
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre-CCIT
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network - Toronto Western Hospital Movement Disorders Clinic
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute and Hospital
• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg og Frederiksberg Hospital
  • Odense, Denmark, 5000
    • Odense Universitetshospital
• Estonia
  • Tallinn, Estonia, 10138
    • East Tallinn Central Hospital
  • Tallinn, Estonia, 11315
    • Astra Team Clinic
  • Tartu, Estonia, 50406
    • Tartu University Hospital
• France
  • Nîmes, France, 30029
    • CHU Caremeau
  • Toulouse, France, 31059
    • Hospital Pierre Paul Rquet, CHU Purpan
  • Nord
    • Lille Cedex, Nord, France
      • Hopital Roger Salengro - CHU Lille
• Germany
  • Berlin, Germany, 13353
    • Charite - Campus Virchow-Klinikum
  • Berlin, Germany, 12 203
    • Charité Universitätsmedizin Berlin - Campus Benjamin Franklin
  • Berlin, Germany, 13088
    • Alexianer St. Joseph-Krankenhaus Berlin-Weißensee, Klinik für Neurologie
  • Berlin, Germany, 13353
    • Charite - Campus Virchow-Klinikum, Klinik fur Neurologie
  • Baden Wuerttemberg
    • Freiburg, Baden Wuerttemberg, Germany, 79106
      • Universitaetsklinikum Freiburg - Klinik fur Neurologie und Neurophysiologie
  • Niedersachsen
    • Westerstede, Niedersachsen, Germany, 26655
      • Gemeinschaftspraxis Dr. med. J. Springub/ W. Schwarz
  • Thueringen
    • Gera, Thueringen, Germany, 07551
      • Praxis Dr. Oehlwein
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
  • Budapest, Hungary, 1033
    • Clinexpert Kft.
  • Pécs, Hungary, 7623
    • Pecsi Tudomanyegyetem, Neurologiai Klinika
  • Tatabanya, Hungary, 2800
    • Szent Borbala Korhaz
• Israel
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center
  • Rehovot, Israel, 7610001
    • Kaplan Medical Center
  • Safed, Israel, 1311001
    • Ziv Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Medical Center
  • Tel HaShomer, Israel, 5262101
    • Chaim Sheba Medical Center
• Italy
  • Ancona, Italy, 60126
    • Azienda Ospedaliero Universitaria Ospedali Riuniti Ancona Umberto I - G.M. Lancisi - G. Salesi, SOD Clinica di Neuroriabilitazione
  • Bologna, Italy, 40139
    • Universita di Bologna-Clinica Neurologica-Dipartimento di Scienze Neurologiche Ospedale Bellaria
  • Catania, Italy, 95123
    • Azienda Ospedaliero - Universitaria Policlinico Vittorio Emanuele. - P.O G. Rodolico, Clinica Neurologica
  • Chieti, Italy, 66100
    • Universita Gabriele D'Annunzio- Cesi-Met
  • Milano, Italy, 20122
    • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
  • Milano, Italy, 58-20132
    • Ospedale San Raffaele I U.O. di Neurologia
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy, 00133
    • Fondazione PTV - Policlinico Tor Vergata I U.O.C. Neurologia
  • Roma, Italy, 00148
    • Ospedale San Giovanni Battista del Sovrano Militare Ordine di Malta
  • Roma, Italy, 00148
    • Ospedale San Giovanni Battista
  • Roma, Italy, 00161
    • Policlinico Umberto I - Universita degli Studi di Roma La Sapienza / Neurologia
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento
  • Roma, Italy, 00185
    • Sapienza University of Rome
  • Salerno, Italy, 84131
    • AOU San Giovanni di Dio e Ruggi d'Aragona
  • Terni, Italy, 5100
    • A.O. Santa Maria
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Istituto Clinico Humanitas - IRCCS
  • Palermo
    • Cefalù, Palermo, Italy, 90015
      • Fondazione Istituto G.Giglio di Cefalù
• New Zealand
  • Christchurch, New Zealand, 8011
    • New Zealand Brain Research Institute
• Poland
  • Katowice, Poland, 40-588
    • Specjalistyczna Praktyka Lekarska prof.Grzegorz Opala
  • Kraków, Poland, 30-510
    • Pratia MCM Krakow
  • Kraków, Poland, 31-505
    • Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej
  • Lublin, Poland, 20-954
    • Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
  • Oświęcim, Poland, 32-600
    • Instytut Zdrowia Dr Boczarska-Jedynak
  • Siemianowice Śląskie, Poland, 41-100
    • Neuro-Care Sp. z o.o. Sp. Komandytowa
  • Warszawa, Poland, 02-777
    • Etg Warszawa
  • Warszawa, Poland, 30-539
    • Specjalistyczne Gabinety Sp. z o.o.
• Portugal
  • Guimaraes, Portugal, 4835-044
    • Hospital Senhora da Oliveira - Guimaraes, EPE
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar e Universitario Lisboa Norte - Hospital de Santa Maria
  • Torres Vedras, Portugal, 2560-280
    • Campus Neurologico Senior
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660037
    • Federal State Budgetary Institution Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency
  • Moscow, Russian Federation, 125284
    • Federal State Budgetary Educational Institution of Additional Professional Education Russian Medical Academy of Continuous Postgraduate Education of the Ministry of Healthcare of the Russian Federation
  • Moscow, Russian Federation, 129128
    • NHI Central Clinical Hospital #2 of JSC Russian Railways N.A. Semashko
  • Novosibirsk, Russian Federation, 630091
    • SBEIHPE Novosibirsk State Medical University
  • Novosibirsk, Russian Federation, 630091
    • City Neurological Center Sibneiromed
  • Saint Petersburg, Russian Federation, 192019
    • Federal State Budgetary Institution National Medical Research Centre of psychiatry and neurology named after V.M. Bekhterev of the Ministry of Healthcare of the Russian Federation
  • Saint Petersburg, Russian Federation, 197376
    • Human Brain Institute RAMS
  • Saint Petersburg, Russian Federation, 197706
    • Saint Petersburg State Budgetary Institution of Healthcare City Hospital # 40 of Kurortnyi Region
  • Smolensk, Russian Federation, 214018
    • Regional State Budgetary Institution of Healthcare Smolensk Regional Clinical Hospital
  • Tatarstan
    • Kazan, Tatarstan, Russian Federation, 420064
      • State Autonomous Institution of Healthcare Republican Clinical Hospital of the Ministry of Healthcare of Republic Tatarstan
• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08222
    • Hospital Universitario Mutua de Terrasa
  • Cadiz, Spain, 11009
    • Hospital Universitario Puerta del Mar
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Guipuzcoa
    • San Sebastián, Guipuzcoa, Spain, 20014
      • Hospital Universitario Donostia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Complejo Hospitalario de Navarra
    • Pamplona, Navarra, Spain, 31008
      • Navarrabiomed Fundacion Miguel Servet
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital de Cruces
• Ukraine
  • Dnipro, Ukraine, 49005
    • Communal Institution Dnipropetrovsk I.I.Mechnikov RCH
  • Kharkiv, Ukraine, 61172
    • Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council
  • Lviv, Ukraine, 79010
    • Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital Dept of Neurology
  • Vinnytsia, Ukraine, 21005
    • CNE Acad O.I. Yushchenko Vinnytsia Reg Psychoneurological Hospital of Vinnytsia Regional Council, Department of Neurology
  • Zaporizhzhia, Ukraine, 69035
    • Communal Institution City Clinical Hospital #6
• United Kingdom
  • London, United Kingdom, W1G 9JF
    • Re:Cognition Health
  • Salford, United Kingdom, M6 8HD
    • Salford Royal
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Plymouth, Devon, United Kingdom, PL6 8BT
      • Re:Cognition Health
  • Greater London
    • London, Greater London, United Kingdom, EC1A 7BE
      • Barts Hospital
    • London, Greater London, United Kingdom, WC1N 3BG
      • The National Hospital for Neurology & Neurosurgery
  • Manchester
    • London, Manchester, United Kingdom, SES 9PJ
      • King's College Hospital
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B16 8LT
      • Re:Cognition Health Ltd
• United States
  • Arizona
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
  • California
    • Long Beach, California, United States, 90806
      • Collaborative Neuroscience Network, LLC
    • Palo Alto, California, United States, 94304
      • Stanford Neuroscience Health Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Colorado Springs Neurological Associates, PC
    • Loveland, Colorado, United States, 80538
      • University of Colorado Health
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital, Dept. of Neurology
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center
    • Boca Raton, Florida, United States, 33487
      • SFM Clinical Research
    • Gainesville, Florida, United States, 32608
      • Fixel Institute for Neurological Diseases
    • Port Charlotte, Florida, United States, 33952
      • Neurostudies, Inc
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Glenview, Illinois, United States, 60026
      • Northshore University Health System
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School
  • New York
    • New York, New York, United States, 10016
      • New York University Langone Health
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Virginia
    • McLean, Virginia, United States, 22101
      • Georgetown University Hospital
  • Washington
    • Spokane, Washington, United States, 99202
      • Inland Northwest Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ampreloxetine; Participants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks.	Drug: ampreloxetine; Oral tablet, QD; Other Names: TD-9855
Placebo Comparator: Placebo; Participants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks.	Drug: Placebo; Oral tablet, QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at 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.	Baseline and Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at 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.	Baseline and Week 4
Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at 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.	Baseline and Week 4
Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at 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.	Baseline and Week 4
Number of Participants Who Experienced at Least One Fall		Up to Week 4

Collaborators and Investigators

• Sponsor: Theravance Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2019
• Primary Completion (Actual): July 21, 2021
• Study Completion (Actual): July 21, 2021

Study Registration Dates

• First Submitted: November 20, 2018
• First Submitted That Met QC Criteria: November 20, 2018
• First Posted (Actual): November 23, 2018

Study Record Updates

• Last Update Posted (Actual): September 14, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: MSA; norepinephrine; Parkinson's disease; PD; dizziness; hypotension; SEQUOIA; fainting; Parkinsonism; PAF; Symptomatic Neurogenic Orthostatic Hypotension; symptomatic nOH; multiple system atrophy; pure autonomic failure; primary autonomic failure; ampreloxetine; low blood pressure; blacking out; lightheadedness; TD-9855; Neurogenic Orthostatic Hypotension; nOH; 0145; 145; 169; 0169; TD9855
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Autonomic Nervous System Diseases; Primary Dysautonomias; Orthostatic Intolerance; Hypotension; Hypotension, Orthostatic; Pure Autonomic Failure
• Other Study ID Numbers: 0169; 2018-003289-15 (EudraCT Number)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No