Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure

NCT03829657 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: 01702018-003941-41
• Study Type: interventional
• Target: 203
• Locations: 17 countries
• Sites: 77

Brief Summary

A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

Conditions

Symptomatic Neurogenic Orthostatic Hypotension; MSA; Parkinson's Disease (PD); Pure Autonomic Failure (PAF)

Keywords

Symptomatic Neurogenic Orthostatic Hypotension; symptomatic nOH; multiple symptom atrophy; MSA; Parkinson's disease; PD; pure autonomic failure; PAF; orthostatic hypotension; OH; REDWOOD; ampreloxetine; low blood pressure; dizziness; fainting; blacking out; lightheadedness; norepinephrine; hypotension; Neurogenic Orthostatic Hypotension; nOH; 170; 0170; 145; 0145; TD-9855; TD9855; Parkinsonism

Outcome Measures

Primary Outcomes (1)

• Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period

  Treatment failure was defined as proportion of participants who met the following criteria at Week 6 following randomization: Change (worsening) from baseline in Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA#1) score of 1.0 point and worsening of disease severity as assessed by a 1-point change in Patient Global Impression of Severity (PGI-S). OHSA Question #1 assessed dizziness, lightheadedness, feeling faint, or feeling like you might blackout. PGI-S assessed patient's impression of disease severity. Least squares mean here is the model-based proportion of participants with treatment failure using logistic regression.

  6-week randomized withdrawal period (Week 16 to Week 22)

Study Arms (3)

ampreloxetine (Open Label (OL))

EXPERIMENTAL

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.

Drug: ampreloxetine

ampreloxetine

EXPERIMENTAL

After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.

Drug: ampreloxetine

Placebo

PLACEBO COMPARATOR

After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.

Drug: Placebo

Interventions

ampreloxetine DRUG

Oral tablet, QD (Daily)

Also known as: TD-9855

ampreloxetine; ampreloxetine (Open Label (OL))

Placebo DRUG

Oral tablet, QD

Placebo

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with ampreloxetine. Only subjects with OHSA#1 score of ≤7 will be eligible for randomization for the double-blind treatment period.
• Subject has a minimum of 80% study medication compliance in Study 0169.
• 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 min of being tilted-up ≥60o from a supine position as determined by a tilt-table test.
• Subject must score at least a 4 on the OHSA#1 at V1.
• 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 Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated position for 30 minutes.

You may not qualify if:

• Subject has a medical, laboratory, or surgical issue(s) deemed by the investigator to be clinically significant.
• Subject has an uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
• Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.
• 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 serotonin norepinephrine reuptake inhibitors (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 V1 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 known or suspected alcohol or substance abuse within the past 12 months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision \[DSM-IV-TR®\] definition of alcohol or substance abuse).
• Subject has a clinically unstable coronary artery disease, or has had a major cardiovascular or neurological event in the past 6 months.
• Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
• 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.

Sponsors & Collaborators

• Theravance Biopharma: lead

Study Sites (82)

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

UC San Diego Movement Disorder Center

La Jolla, California, 92307, United States

Location

Stanford Neuroscience Health Center

Palo Alto, California, 94304, United States

Location

Colorado Springs Neurological Associates, PC

Colorado Springs, Colorado, 80907, United States

Location

Parkinson's Disease and Movement Disorders Center

Boca Raton, Florida, 33486, United States

Location

SFM Clinical Research, LLC

Boca Raton, Florida, 33487, United States

Location

Neurostudies, Inc

Port Charlotte, Florida, 33952, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

NorthShore University Health System

Glenview, Illinois, 60026, United States

Location

University of Kansas Medical Center Research Institute, Inc.

Kansas City, Kansas, 66160, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

New York University Langone Health

New York, New York, 10016, United States

Location

Wake Forest University Baptist Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati Medical Center (UCGNI)

Cincinnati, Ohio, 45219, United States

Location

Ohio State University - Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Georgetown University Hospital

McLean, Virginia, 22101, United States

Location

Inland Northwest Research

Spokane, Washington, 99202, United States

Location

Concord Hospital, Neurosciences Department

Concord, New South Wales, 02139, Australia

Location

Clinical Trials Centre, Level 3 Monash Health Translational Precinct Building Monash Medical Centre

Clayton, Victoria, 3168, Australia

Location

The Royal Melbourne Hospital Neurology Department

Parkville, Victoria, 3050, Australia

Location

Perron Institute for Neurological and Translational Science

Nedlands, Western Australia, 6009, Australia

Location

Medizinische Universitat Innsbruck, Abteilung fur Neurologie

Innsbruck, 6020, Austria

Location

Universitatsklinikum Tulln Abteilung fur Neurologie

Tulln, 3430, Austria

Location

MHATNP Sv. Naum EAD Clinic of Neurological Diseases for Locomotor Disorders

Sofia, 1113, Bulgaria

Location

University of Calgary Teaching Research and Wellness Building

Calgary, Alberta, T2N 4Z6, Canada

Location

Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

Location

Montreal Neurological Institute & Hospital

Montreal, Quebec, H3A 2B4, Canada

Location

Bispebjerg Hospital

Copenhagen, 2400, Denmark

Location

Odense Universitetshospital

Odense, 5000, Denmark

Location

East Tallinn Central Hospital

Tallinn, 10138, Estonia

Location

Astra Team Clinic

Tallinn, 11315, Estonia

Location

Tartu University Hospital

Tartu, 50406, Estonia

Location

CHU de Nîmes - Hôpital Caremeau

Nîmes, 30029, France

Location

Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin

Berlin, 12203, Germany

Location

Charite - Campus Virchow-Klinikum, Klinik fur Neurologie

Berlin, 13353, Germany

Location

Praxis Dr. med. Christian Oehlwein

Gera, 7551, Germany

Location

Semmelweis Egyetem, Neurologiai Klinika

Budapest, 1083, Hungary

Location

Rabin Medical Center, Beilinson Campus

Petah Tikva, 4941492, Israel

Location

Kaplan Medical Center

Rehovot, 76100, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Universita di Bologna-Clinica Neurologica - Dipt di Scienze Neurologiche Ospedale Bellaria

Bologna, 40139, Italy

Location

Azienda Ospedaliera Universitaria Policlinico - Vittorio Emanuele (Presidio Gaspare Rodolico)

Catania, 95125, Italy

Location

Universita degli studi Gabriele D' Annunzio Chieti

Chieti, 66100, Italy

Location

Fondazione IRCCS CA Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Azienda Ospedaliero-Universitaria Pisana- Ospedale S. Chiara, U.O. di Neurologia - Neurofisiopatologia

Pisa, 56126, Italy

Location

Fondazione PTV - Policlinico Tor Vergata I U.0.C. Neurologia

Roma, 00133, Italy

Location

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

Roma, 00168, Italy

Location

AOU San Giovanni di Dio e Ruggi d'Aragona

Salerno, 84131, Italy

Location

A.O. Santa Maria

Terni, 05100, Italy

Location

New Zealand Brain Research Institute

Christchurch, 8011, New Zealand

Location

Specjalistyczna Praktyka Lekarska, Prof. Grzegorz Opala

Katowice, 40-588, Poland

Location

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

Krakow, 31-505, Poland

Location

Instytut Zdrowia dr Boczarska-Jedynak

Oświęcim, 32-600, Poland

Location

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

Siemianowice Śląskie, 41-100, Poland

Location

ETG Warszawa

Warsaw, 02-777, Poland

Location

Specjalistyczne Gabinety sp. z o.o.

Warsaw, 30-539, Poland

Location

Hospital da Senhora da Oliveira Guimarães

Guimarães, 4835-044, Portugal

Location

CNS-Campus Neurologico Senior

Torres Vedras, 2560-280, Portugal

Location

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

Saint Petersburg, Sestroretsk, 197706, Russia

Location

FSBI Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency

Krasnoyarsk, 660037, Russia

Location

State Budgetary Institution of Healthcare of Novosibirsk region City Clinical Hospital #34

Novosibirsk, 630054, Russia

Location

City Neurological Center Sibneiromed, LLC

Novosibirsk, 630091, Russia

Location

FSBI National Medical Research Centre of psychiatry and neurology named after V.M. Bekhterev of the MOH of the Russian Federation

Saint Petersburg, 192019, Russia

Location

FSBI of Science Institute of Human Brain named after N .P. Bekhtereva of Russian Academy of Sciences

Saint Petersburg, 197376, Russia

Location

Hospital Universitario Mutua de Terrasa

Terrassa, Barcelona, 08221, Spain

Location

Complejo Hospitalario de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital de Cruces

Bilbao, Vizcaya, 48903, Spain

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Universitario de La Princesa

Madrid, 28006, Spain

Location

Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council

Kharkiv, 61172, Ukraine

Location

Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital

Lviv, 79010, Ukraine

Location

Communal Institution Acad. O.I. Yuschenko VRPsH Vinnytsia M.I. Pyrogov NMU Ch of ND with the Course of Neurosurgery

Vinnytsia, 21005, Ukraine

Location

Royal Devon and Exeter Hospital NHS Trust

Exeter, Devon, EX2 5DW, United Kingdom

Location

Cognition Health Unit 2

Plymouth, Devon, PL6 8BT, United Kingdom

Location

Salford Royal NHS Foundation Trust

Salford, Greater Manchester, M6 8HD, United Kingdom

Location

Clinical Research Centre, William Harvey Heart Centre

London, EC1M 6BQ, United Kingdom

Location

King's College Hospital

London, SE5 9RS, United Kingdom

Location

Re:Cognition Health Ltd

London, W1G 9JF, United Kingdom

Location

The National Hospital for Neurology & Neurosurgery

London, WC1N 3BG, United Kingdom

Location

MeSH Terms

Conditions

Parkinson Disease; Pure Autonomic Failure; Hypotension, Orthostatic; Hypotension; Dizziness; Syncope; Parkinsonian Disorders

Interventions

ampreloxetine

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Orthostatic Intolerance; Vascular Diseases; Cardiovascular Diseases; Sensation Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations

Limitations and Caveats

De Novo participants in the OL treatment period had limited follow-up due to early termination of the study.

Results Point of Contact

• Title: Medical Monitor
• Organization: Theravance Biopharma Ireland Limited

medinfo@theravance.com

855 633 8479

Study Officials

• Medical Monitor

  Theravance Biopharma

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open Label Extension followed by Randomized Parallel Assignment

Study Record Dates

• First Submitted: January 10, 2019
• First Posted: February 4, 2019
• Study Start: February 22, 2019
• Primary Completion: November 10, 2021
• Study Completion: November 10, 2021
• Last Updated: January 20, 2023
• Results First Posted: January 20, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

BU (1); NZ (1); AU (4); RU (6); DK (2); PT (2); UA (3); GB (7); FR (1); IL (3); IT (9); CA (3); DE (3); PL (6); US (20); HU (1); ES (5)