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

NCT ID: NCT03750552

Last Updated: 2022-09-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 195 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-24
• Study Completion Date: 2021-07-21

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).

Conditions

Symptomatic Neurogenic Orthostatic Hypotension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

ampreloxetine

Participants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks.

Group Type: EXPERIMENTAL

ampreloxetine

Intervention Type: DRUG

Oral tablet, QD

Placebo

Participants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral tablet, QD

Interventions

ampreloxetine

Oral tablet, QD

Intervention Type: DRUG

Placebo

Oral tablet, QD

Intervention Type: DRUG

Other Intervention Names

TD-9855

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.

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Theravance Biopharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Theravance Biopharma

Locations

Banner Sun Health Research Institute

Sun City, Arizona, United States

Collaborative Neuroscience Network, LLC

Long Beach, California, United States

Stanford Neuroscience Health Center

Palo Alto, California, United States

Colorado Springs Neurological Associates, PC

Colorado Springs, Colorado, United States

University of Colorado Health

Loveland, Colorado, United States

Georgetown University Hospital, Dept. of Neurology

Washington D.C., District of Columbia, United States

Parkinson's Disease and Movement Disorders Center

Boca Raton, Florida, United States

SFM Clinical Research

Boca Raton, Florida, United States

Fixel Institute for Neurological Diseases

Gainesville, Florida, United States

Neurostudies, Inc

Port Charlotte, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

NorthShore University Health System

Glenview, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

Rutgers New Jersey Medical School

Newark, New Jersey, United States

New York University Langone Health

New York, New York, United States

University of Cincinnati Medical Center

Cincinnati, Ohio, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Georgetown University Hospital

McLean, Virginia, United States

Inland Northwest Research

Spokane, Washington, United States

Concord Hospital

Concord, New South Wales, Australia

Royal Brisbane and Women's Hospital

Herston, Queensland, Australia

Monash Health - Clinical Trials Centre

Clayton, Victoria, Australia

The Royal Melbourne Hospital

Parkville, Victoria, Australia

Perron Institute for Neurological and Translational Science, QEII Medical Centre

Nedlands, , Australia

Medizinische Universitat Innsbruck Abteilung Fur Neurologie

Innsbruck, , Austria

Universitätsklinikum Tulln

Tulln, , Austria

Wilhelminenspital Wien Abteilung fur Neurologie

Vienna, , Austria

UMHAT Sveti Georgi EAD Clinic of Neurological Diseases

Plovdiv, , Bulgaria

MHATNP Sv.Naum, EAD

Sofia, , Bulgaria

UMHAT Alexandrovska EAD Clinic of Neurological Diseases

Sofia, , Bulgaria

University of Calgary

Calgary, Alberta, Canada

London Health Sciences Centre-CCIT

London, Ontario, Canada

University Health Network - Toronto Western Hospital Movement Disorders Clinic

Toronto, Ontario, Canada

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada

Bispebjerg og Frederiksberg Hospital

Copenhagen, , Denmark

Odense Universitetshospital

Odense, , Denmark

East Tallinn Central Hospital

Tallinn, , Estonia

Astra Team Clinic

Tallinn, , Estonia

Tartu University Hospital

Tartu, , Estonia

Hopital Roger Salengro - CHU Lille

Lille, Nord, France

CHU Caremeau

Nîmes, , France

Hospital Pierre Paul Rquet, CHU Purpan

Toulouse, , France

Universitaetsklinikum Freiburg - Klinik fur Neurologie und Neurophysiologie

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Gemeinschaftspraxis Dr. med. J. Springub/ W. Schwarz

Westerstede, Lower Saxony, Germany

Praxis Dr. Oehlwein

Gera, Thuringia, Germany

Charite Universitatsmedizin Berlin - Campus Benjamin Franklin

Berlin, , Germany

Alexianer St. Joseph-Krankenhaus Berlin-Weißensee, Klinik für Neurologie

Berlin, , Germany

Charite - Campus Virchow-Klinikum, Klinik fur Neurologie

Berlin, , Germany

Charite - Campus Virchow-Klinikum

Berlin, , Germany

Clinexpert Kft.

Budapest, , Hungary

Semmelweis Egyetem

Budapest, , Hungary

Pecsi Tudomanyegyetem, Neurologiai Klinika

Pécs, , Hungary

Szent Borbala Korhaz

Tatabánya, , Hungary

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 Litwinsky, , Israel

Istituto Clinico Humanitas - IRCCS

Rozzano, Milano, Italy

Fondazione Istituto G.Giglio di Cefalù

Cefalù, Palermo, 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

Universita Gabriele D'Annunzio- Cesi-Met

Chieti, , Italy

Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Ospedale San Raffaele I U.O. di Neurologia

Milan, , Italy

Azienda Ospedaliero Universitaria Pisana

Pisa, , Italy

Fondazione PTV - Policlinico Tor Vergata I U.O.C. Neurologia

Roma, , Italy

Ospedale San Giovanni Battista del Sovrano Militare Ordine di Malta

Roma, , Italy

Ospedale San Giovanni Battista

Roma, , Italy

Policlinico Umberto I - Universita degli Studi di Roma La Sapienza / Neurologia

Roma, , Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento

Roma, , Italy

Sapienza University of Rome

Roma, , Italy

AOU San Giovanni di Dio e Ruggi d'Aragona

Salerno, , Italy

A.O. Santa Maria

Terni, , Italy

New Zealand Brain Research Institute

Christchurch, , New Zealand

Specjalistyczna Praktyka Lekarska prof.Grzegorz Opala

Katowice, , Poland

PRATIA MCM Kraków

Krakow, , Poland

Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej

Krakow, , Poland

Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie

Lublin, , Poland

Instytut Zdrowia dr Boczarska-Jedynak

Oświęcim, , Poland

NEURO-CARE Sp. z o.o. Sp. Komandytowa

Siemianowice Śląskie, , Poland

ETG Warszawa

Warsaw, , Poland

Specjalistyczne Gabinety sp. z o.o.

Warsaw, , Poland

Hospital Senhora da Oliveira - Guimaraes, EPE

Guimarães, , Portugal

Centro Hospitalar e Universitario Lisboa Norte - Hospital de Santa Maria

Lisbon, , Portugal

Campus Neurologico Senior

Torres Vedras, , Portugal

State Autonomous Institution of Healthcare Republican Clinical Hospital of the Ministry of Healthcare of Republic Tatarstan

Kazan', Tatarstan Republic, Russia

Federal State Budgetary Institution Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency

Krasnoyarsk, , Russia

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, , Russia

NHI Central Clinical Hospital #2 of JSC Russian Railways N.A. Semashko

Moscow, , Russia

City Neurological Center Sibneiromed

Novosibirsk, , Russia

SBEIHPE Novosibirsk State Medical University

Novosibirsk, , Russia

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, , Russia

Human Brain Institute RAMS

Saint Petersburg, , Russia

Saint Petersburg State Budgetary Institution of Healthcare City Hospital # 40 of Kurortnyi Region

Saint Petersburg, , Russia

Regional State Budgetary Institution of Healthcare Smolensk Regional Clinical Hospital

Smolensk, , Russia

Hospital Universitario Donostia

San Sebastián, Guipuzcoa, Spain

Complejo Hospitalario de Navarra

Pamplona, Navarre, Spain

Navarrabiomed Fundacion Miguel Servet

Pamplona, Navarre, 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 Universitario de La Princesa

Madrid, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

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, , Ukraine

Royal Devon and Exeter Hospital

Exeter, Devon, United Kingdom

Re:Cognition Health

Plymouth, Devon, United Kingdom

Barts Hospital

London, Greater London, United Kingdom

The National Hospital for Neurology & Neurosurgery

London, Greater London, United Kingdom

King's College Hospital

London, Manchester, United Kingdom

Re:Cognition Health Ltd

Birmingham, West Midlands, United Kingdom

Re:Cognition Health

London, , United Kingdom

Salford Royal

Salford, , United Kingdom

Countries

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

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-003289-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

0169

Identifier Type: -

Identifier Source: org_study_id