Symptomatic Neurogenic Orthostatic HypotensionPhase 3SEQUOIANCT03750552
Clinical Effect of Ampreloxetine (TD-9855) for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
A Phase 3 study testing ampreloxetine in people with Symptomatic Neurogenic Orthostatic Hypotension, run by Theravance Biopharma at 125 sites in 19 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 years and older
- Conditions the study is for
- Symptomatic Neurogenic Orthostatic Hypotension
- What is being tested?
- ampreloxetine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 195 participants
- Where
- 125 sitesin 19 countries
- Study dates
- 24 Jan 2019to 21 Jul 2021
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
125 sites in 19 countries.
125 sites in 19 countries
United States23 sites
Parkinson's Disease and Movement Disorders Center
Boca Raton, Florida, 33486
SFM Clinical Research
Boca Raton, Florida, 33487
Rush University Medical Center
Chicago, Illinois, 60612
University of Cincinnati Medical Center
Cincinnati, Ohio, 45219
Colorado Springs Neurological Associates, PC
Colorado Springs, Colorado, 80907
The Ohio State University Wexner Medical Center
Columbus, Ohio, 43210
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Fixel Institute for Neurological Diseases
Gainesville, Florida, 32608
NorthShore University Health System
Glenview, Illinois, 60026
University of Kansas Medical Center
Kansas City, Kansas, 66160
Collaborative Neuroscience Network, LLC
Long Beach, California, 90806
University of Colorado Health
Loveland, Colorado, 80538
Georgetown University Hospital
McLean, Virginia, 22101
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
New York University Langone Health
New York, New York, 10016
Rutgers New Jersey Medical School
Newark, New Jersey, 07103
Stanford Neuroscience Health Center
Palo Alto, California, 94304
Neurostudies, Inc
Port Charlotte, Florida, 33952
Oregon Health & Science University
Portland, Oregon, 97239
Mayo Clinic - Rochester
Rochester, Minnesota, 55905
Inland Northwest Research
Spokane, Washington, 99202
Banner Sun Health Research Institute
Sun City, Arizona, 85351
Georgetown University Hospital, Dept. of Neurology
Washington D.C., District of Columbia, 20007
Italy17 sites
Azienda Ospedaliero Universitaria Ospedali Riuniti Ancona Umberto I - G.M. Lancisi - G. Salesi, SOD Clinica di Neuroriabilitazione
Ancona, 60126
Universita di Bologna-Clinica Neurologica-Dipartimento di Scienze Neurologiche Ospedale Bellaria
Bologna, 40139
Azienda Ospedaliero - Universitaria Policlinico Vittorio Emanuele. - P.O G. Rodolico, Clinica Neurologica
Catania, 95123
Fondazione Istituto G.Giglio di Cefalù
Cefalù, Palermo, 90015
Universita Gabriele D'Annunzio- Cesi-Met
Chieti, 66100
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
Milan, 20122
Ospedale San Raffaele I U.O. di Neurologia
Milan, 58-20132
Azienda Ospedaliero Universitaria Pisana
Pisa, 56126
Fondazione PTV - Policlinico Tor Vergata I U.O.C. Neurologia
Roma, 00133
Ospedale San Giovanni Battista del Sovrano Militare Ordine di Malta
Roma, 00148
Ospedale San Giovanni Battista
Roma, 00148
Policlinico Umberto I - Universita degli Studi di Roma La Sapienza / Neurologia
Roma, 00161
Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento
Roma, 00168
Sapienza University of Rome
Roma, 00185
Istituto Clinico Humanitas - IRCCS
Rozzano, Milano, 20089
AOU San Giovanni di Dio e Ruggi d'Aragona
Salerno, 84131
A.O. Santa Maria
Terni, 5100
Spain11 sites
Hospital de Cruces
Barakaldo, Vizcaya, 48903
Hospital del Mar
Barcelona, 08003
Hospital Universitari Vall d'Hebron
Barcelona, 08035
Hospital Universitario Mutua de Terrasa
Barcelona, 08222
Hospital Universitario Puerta del Mar
Cadiz, 11009
Hospital Universitario de La Princesa
Madrid, 28006
Hospital General Universitario Gregorio Marañon
Madrid, 28007
Complejo Hospitalario de Navarra
Pamplona, Navarre, 31008
Navarrabiomed Fundacion Miguel Servet
Pamplona, Navarre, 31008
Hospital Universitario Donostia
San Sebastián, Guipuzcoa, 20014
Hospital Universitario Virgen del Rocio
Seville, 41013
Russia10 sites
State Autonomous Institution of Healthcare Republican Clinical Hospital of the Ministry of Healthcare of Republic Tatarstan
Kazan', Tatarstan Republic, 420064
Federal State Budgetary Institution Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency
Krasnoyarsk, 660037
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, 125284
NHI Central Clinical Hospital #2 of JSC Russian Railways N.A. Semashko
Moscow, 129128
City Neurological Center Sibneiromed
Novosibirsk, 630091
SBEIHPE Novosibirsk State Medical University
Novosibirsk, 630091
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, 192019
Human Brain Institute RAMS
Saint Petersburg, 197376
Saint Petersburg State Budgetary Institution of Healthcare City Hospital # 40 of Kurortnyi Region
Saint Petersburg, 197706
Regional State Budgetary Institution of Healthcare Smolensk Regional Clinical Hospital
Smolensk, 214018
Poland8 sites
Specjalistyczna Praktyka Lekarska prof.Grzegorz Opala
Katowice, 40-588
PRATIA MCM Kraków
Krakow, 30-510
Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej
Krakow, 31-505
Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie
Lublin, 20-954
Instytut Zdrowia dr Boczarska-Jedynak
Oświęcim, 32-600
NEURO-CARE Sp. z o.o. Sp. Komandytowa
Siemianowice Śląskie, 41-100
ETG Warszawa
Warsaw, 02-777
Specjalistyczne Gabinety sp. z o.o.
Warsaw, 30-539
United Kingdom8 sites
Re:Cognition Health Ltd
Birmingham, West Midlands, B16 8LT
Royal Devon and Exeter Hospital
Exeter, Devon, EX2 5DW
Barts Hospital
London, Greater London, EC1A 7BE
The National Hospital for Neurology & Neurosurgery
London, Greater London, WC1N 3BG
King's College Hospital
London, Manchester, SES 9PJ
Re:Cognition Health
London, W1G 9JF
Re:Cognition Health
Plymouth, Devon, PL6 8BT
Salford Royal
Salford, M6 8HD
Germany7 sites
Charite Universitatsmedizin Berlin - Campus Benjamin Franklin
Berlin, 12 203
Alexianer St. Joseph-Krankenhaus Berlin-Weißensee, Klinik für Neurologie
Berlin, 13088
Charite - Campus Virchow-Klinikum, Klinik fur Neurologie
Berlin, 13353
Charite - Campus Virchow-Klinikum
Berlin, 13353
Universitaetsklinikum Freiburg - Klinik fur Neurologie und Neurophysiologie
Freiburg im Breisgau, Baden-Wurttemberg, 79106
Praxis Dr. Oehlwein
Gera, Thuringia, 07551
Gemeinschaftspraxis Dr. med. J. Springub/ W. Schwarz
Westerstede, Lower Saxony, 26655
Australia5 sites
Monash Health - Clinical Trials Centre
Clayton, Victoria, 3168
Concord Hospital
Concord, New South Wales, 2139
Royal Brisbane and Women's Hospital
Herston, Queensland, 4029
Perron Institute for Neurological and Translational Science, QEII Medical Centre
Nedlands, 6009
The Royal Melbourne Hospital
Parkville, Victoria, 3050
Israel5 sites
Rabin Medical Center
Petah Tikva, 4941492
Kaplan Medical Center
Rehovot, 7610001
Ziv Medical Center
Safed, 1311001
Tel Aviv Medical Center
Tel Aviv, 6423906
Chaim Sheba Medical Center
Tel Litwinsky, 5262101
Ukraine5 sites
Communal Institution Dnipropetrovsk I.I.Mechnikov RCH
Dnipro, 49005
Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council
Kharkiv, 61172
Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital Dept of Neurology
Lviv, 79010
CNE Acad O.I. Yushchenko Vinnytsia Reg Psychoneurological Hospital of Vinnytsia Regional Council, Department of Neurology
Vinnytsia, 21005
Communal Institution City Clinical Hospital #6
Zaporizhzhya, 69035
Canada4 sites
University of Calgary
Calgary, Alberta, T2N 4Z6
London Health Sciences Centre-CCIT
London, Ontario, N6A 5A5
Montreal Neurological Institute and Hospital
Montreal, Quebec, H3A 2B4
University Health Network - Toronto Western Hospital Movement Disorders Clinic
Toronto, Ontario, M5T 2S8
Hungary4 sites
Clinexpert Kft.
Budapest, 1033
Semmelweis Egyetem
Budapest, 1083
Pecsi Tudomanyegyetem, Neurologiai Klinika
Pécs, 7623
Szent Borbala Korhaz
Tatabánya, 2800
Austria3 sites
Medizinische Universitat Innsbruck Abteilung Fur Neurologie
Innsbruck, 6020
Universitätsklinikum Tulln
Tulln, 3430
Wilhelminenspital Wien Abteilung fur Neurologie
Vienna, 1160
Bulgaria3 sites
UMHAT Sveti Georgi EAD Clinic of Neurological Diseases
Plovdiv, 4000
MHATNP Sv.Naum, EAD
Sofia, 1113
UMHAT Alexandrovska EAD Clinic of Neurological Diseases
Sofia, 1431
Estonia3 sites
East Tallinn Central Hospital
Tallinn, 10138
Astra Team Clinic
Tallinn, 11315
Tartu University Hospital
Tartu, 50406
France3 sites
Hopital Roger Salengro - CHU Lille
Lille, Nord
CHU Caremeau
Nîmes, 30029
Hospital Pierre Paul Rquet, CHU Purpan
Toulouse, 31059
Portugal3 sites
Hospital Senhora da Oliveira - Guimaraes, EPE
Guimarães, 4835-044
Centro Hospitalar e Universitario Lisboa Norte - Hospital de Santa Maria
Lisbon, 1649-035
Campus Neurologico Senior
Torres Vedras, 2560-280
Denmark2 sites
Bispebjerg og Frederiksberg Hospital
Copenhagen, 2400
Odense Universitetshospital
Odense, 5000
About this study
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
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.
Read the 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).
- Being tested
- ampreloxetine, Placebo
- 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
- Medical subject headings
- Multiple System Atrophy, Parkinson Disease, Pure Autonomic Failure, Hypotension, Dizziness, Syncope, Parkinsonian Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ampreloxetineDrug
Also called TD-9855
Oral tablet, QD
PlaceboDrug
Oral tablet, QD
| Study group | Role | What they receive |
|---|---|---|
| ampreloxetine | Experimental | Participants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks. Receives: Drug: ampreloxetine |
| Placebo | Placebo comparator | Participants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and Week 4
Secondary outcomes (4)
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.
Measured: 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.
Measured: 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.
Measured: Baseline and Week 4
Number of Participants Who Experienced at Least One Fall
Measured: Up to Week 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2018
- Study start24 Jan 2019
- Primary completion21 Jul 2021
- Study completion21 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Symptomatic Neurogenic Orthostatic HypotensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Parallel assignment
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 195 participants (actual)
Sponsor and investigators
- Lead sponsor
- Theravance Biopharma
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Monitor, Study director, Theravance Biopharma
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03750552
- Sponsor's protocol ID
- 0169
- Other IDs
- 2018-003289-15, 2018
- Acronym
- SEQUOIA
- Status last verified
- Aug 2022
- First submitted
- 20 Nov 2018
- Last updated
- 14 Sep 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.
Publications
Freeman R, Kaufmann H, Biaggioni I, Iodice V, Jordan J, Vickery R, Geurin T, Kmiecik MJ, Norcliffe-Kaufmann L. Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial. Neurology. 2026 Aug 11;107(3):e218284. doi: 10.1212/WNL.0000000000218284. Epub 2026 Jul 20.
PubMed 42475649