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

Symptomatic Neurogenic Orthostatic Hypotension Clinical Trial

— SEQUOIA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03750552
• Other study ID #: 0169
• Secondary ID: 2018-003289-15
• Status: Completed
• Phase: Phase 3
• Start date: January 24, 2019
• Est. completion date: July 21, 2021

Study information

• Verified date: August 2022
• Source: Theravance Biopharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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 information / eligibility

• Status: Completed
• Enrollment: 195
• Est. completion date: July 21, 2021
• Est. primary completion date: July 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypotension
• Hypotension, Orthostatic
• Pure Autonomic Failure
• Symptomatic Neurogenic Orthostatic Hypotension

Intervention

Drug:
• ampreloxetine
Oral tablet, QD
• Placebo
Oral tablet, QD

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Theravance Biopharma

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  Canada,  Denmark,  Estonia,  France,  Germany,  Hungary,  Israel,  Italy,  New Zealand,  Poland,  Portugal,  Russian Federation,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Number of Participants Who Experienced at Least One Fall		Up to Week 4