Clinical trial NCT03750552: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Symptomatic Neurogenic Orthostatic Hypotension
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
Neurogenic Orthostatic Hypotension
nOH
0145
145
169
0169
TD9855
Lead sponsor: Theravance Biopharma
Sponsor class: INDUSTRY
First posted: 2018-11-23
Enrollment: 195
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4
timeFrame: Baseline and Week 4
Secondary outcomes:
measure: Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4
timeFrame: Baseline and Week 4
measure: Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4
timeFrame: Baseline and Week 4
measure: Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4
timeFrame: Baseline and Week 4
measure: Number of Participants Who Experienced at Least One Fall
timeFrame: Up to Week 4
Other outcomes:
Locations:
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Long Beach
country: United States
facility: Collaborative Neuroscience Network, LLC
state: California
city: Palo Alto
country: United States
facility: Stanford Neuroscience Health Center
state: California
city: Colorado Springs
country: United States
facility: Colorado Springs Neurological Associates, PC
state: Colorado
city: Loveland
country: United States
facility: University of Colorado Health
state: Colorado
city: Washington
country: United States
facility: Georgetown University Hospital, Dept. of Neurology
state: District of Columbia
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center
state: Florida
city: Boca Raton
country: United States
facility: SFM Clinical Research
state: Florida
city: Gainesville
country: United States
facility: Fixel Institute for Neurological Diseases
state: Florida
city: Port Charlotte
country: United States
facility: Neurostudies, Inc
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Glenview
country: United States
facility: NorthShore University Health System
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: McLean
country: United States
facility: Georgetown University Hospital
state: Virginia
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Concord
country: Australia
facility: Concord Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Health - Clinical Trials Centre
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Perron Institute for Neurological and Translational Science, QEII Medical Centre
city: Innsbruck
country: Austria
facility: Medizinische Universitat Innsbruck Abteilung Fur Neurologie
city: Tulln
country: Austria
facility: Universitätsklinikum Tulln
city: Wien
country: Austria
facility: Wilhelminenspital Wien Abteilung fur Neurologie
city: Plovdiv
country: Bulgaria
facility: UMHAT Sveti Georgi EAD Clinic of Neurological Diseases
city: Sofia
country: Bulgaria
facility: MHATNP Sv.Naum, EAD
city: Sofia
country: Bulgaria
facility: UMHAT Alexandrovska EAD Clinic of Neurological Diseases
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre-CCIT
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital Movement Disorders Clinic
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Copenhagen
country: Denmark
facility: Bispebjerg og Frederiksberg Hospital
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital
city: Tallinn
country: Estonia
facility: Astra Team Clinic
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Lille Cedex
country: France
facility: Hopital Roger Salengro - CHU Lille
state: Nord
city: Nîmes
country: France
facility: CHU Caremeau
city: Toulouse
country: France
facility: Hospital Pierre Paul Rquet, CHU Purpan
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg - Klinik fur Neurologie und Neurophysiologie
state: Baden Wuerttemberg
city: Westerstede
country: Germany
facility: Gemeinschaftspraxis Dr. med. J. Springub/ W. Schwarz
state: Niedersachsen
city: Gera
country: Germany
facility: Praxis Dr. Oehlwein
state: Thueringen
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Alexianer St. Joseph-Krankenhaus Berlin-Weißensee, Klinik für Neurologie
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum, Klinik fur Neurologie
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum
city: Budapest
country: Hungary
facility: Clinexpert Kft.
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Pécs
country: Hungary
facility: Pecsi Tudomanyegyetem, Neurologiai Klinika
city: Tatabanya
country: Hungary
facility: Szent Borbala Korhaz
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Safed
country: Israel
facility: Ziv Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Medical Center
city: Tel HaShomer
country: Israel
facility: Chaim Sheba Medical Center
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas - IRCCS
state: Milano
city: Cefalù
country: Italy
facility: Fondazione Istituto G.Giglio di Cefalù
state: Palermo
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti Ancona Umberto I - G.M. Lancisi - G. Salesi, SOD Clinica di Neuroriabilitazione
city: Bologna
country: Italy
facility: Universita di Bologna-Clinica Neurologica-Dipartimento di Scienze Neurologiche Ospedale Bellaria
city: Catania
country: Italy
facility: Azienda Ospedaliero - Universitaria Policlinico Vittorio Emanuele. - P.O G. Rodolico, Clinica Neurologica
city: Chieti
country: Italy
facility: Universita Gabriele D'Annunzio- Cesi-Met
city: Milano
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Ospedale San Raffaele I U.O. di Neurologia
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Roma
country: Italy
facility: Fondazione PTV - Policlinico Tor Vergata I U.O.C. Neurologia
city: Roma
country: Italy
facility: Ospedale San Giovanni Battista del Sovrano Militare Ordine di Malta
city: Roma
country: Italy
facility: Ospedale San Giovanni Battista
city: Roma
country: Italy
facility: Policlinico Umberto I - Universita degli Studi di Roma La Sapienza / Neurologia
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento
city: Roma
country: Italy
facility: Sapienza University of Rome
city: Salerno
country: Italy
facility: AOU San Giovanni di Dio e Ruggi d'Aragona
city: Terni
country: Italy
facility: A.O. Santa Maria
city: Christchurch
country: New Zealand
facility: New Zealand Brain Research Institute
city: Katowice
country: Poland
facility: Specjalistyczna Praktyka Lekarska prof.Grzegorz Opala
city: Kraków
country: Poland
facility: PRATIA MCM Kraków
city: Kraków
country: Poland
facility: Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie
city: Oświęcim
country: Poland
facility: Instytut Zdrowia dr Boczarska-Jedynak
city: Siemianowice Śląskie
country: Poland
facility: NEURO-CARE Sp. z o.o. Sp. Komandytowa
city: Warszawa
country: Poland
facility: ETG Warszawa
city: Warszawa
country: Poland
facility: Specjalistyczne Gabinety sp. z o.o.
city: Guimaraes
country: Portugal
facility: Hospital Senhora da Oliveira - Guimaraes, EPE
city: Lisboa
country: Portugal
facility: Centro Hospitalar e Universitario Lisboa Norte - Hospital de Santa Maria
city: Torres Vedras
country: Portugal
facility: Campus Neurologico Senior
city: Kazan
country: Russian Federation
facility: State Autonomous Institution of Healthcare Republican Clinical Hospital of the Ministry of Healthcare of Republic Tatarstan
state: Tatarstan
city: Krasnoyarsk
country: Russian Federation
facility: Federal State Budgetary Institution Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency
city: Moscow
country: Russian Federation
facility: 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
city: Moscow
country: Russian Federation
facility: NHI Central Clinical Hospital #2 of JSC Russian Railways N.A. Semashko
city: Novosibirsk
country: Russian Federation
facility: City Neurological Center Sibneiromed
city: Novosibirsk
country: Russian Federation
facility: SBEIHPE Novosibirsk State Medical University
city: Saint Petersburg
country: Russian Federation
facility: 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
city: Saint Petersburg
country: Russian Federation
facility: Human Brain Institute RAMS
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Budgetary Institution of Healthcare City Hospital # 40 of Kurortnyi Region
city: Smolensk
country: Russian Federation
facility: Regional State Budgetary Institution of Healthcare Smolensk Regional Clinical Hospital
city: San Sebastián
country: Spain
facility: Hospital Universitario Donostia
state: Guipuzcoa
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
state: Navarra
city: Pamplona
country: Spain
facility: Navarrabiomed Fundacion Miguel Servet
state: Navarra
city: Barakaldo
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitario Mutua de Terrasa
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Dnipro
country: Ukraine
facility: Communal Institution Dnipropetrovsk I.I.Mechnikov RCH
city: Kharkiv
country: Ukraine
facility: Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council
city: Lviv
country: Ukraine
facility: Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital Dept of Neurology
city: Vinnytsia
country: Ukraine
facility: CNE Acad O.I. Yushchenko Vinnytsia Reg Psychoneurological Hospital of Vinnytsia Regional Council, Department of Neurology
city: Zaporizhzhia
country: Ukraine
facility: Communal Institution City Clinical Hospital #6
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: Devon
city: Plymouth
country: United Kingdom
facility: Re:Cognition Health
state: Devon
city: London
country: United Kingdom
facility: Barts Hospital
state: Greater London
city: London
country: United Kingdom
facility: The National Hospital for Neurology & Neurosurgery
state: Greater London
city: London
country: United Kingdom
facility: King's College Hospital
state: Manchester
city: Birmingham
country: United Kingdom
facility: Re:Cognition Health Ltd
state: West Midlands
city: London
country: United Kingdom
facility: Re:Cognition Health
city: Salford
country: United Kingdom
facility: Salford Royal
Study officials:
affiliation: Theravance Biopharma
name: Medical Monitor
role: STUDY_DIRECTOR
References: