Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic nOH in Participants With Multiple System Atrophy

NCT05696717 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: 2022-003903-14
• Study Type: interventional
• Target: 102
• Locations: 18 countries
• Sites: 75

Brief Summary

This is a Phase 3, multi-center, randomized withdrawal study to evaluate the efficacy and durability of ampreloxetine in participants with MSA and symptomatic nOH after 20 weeks of treatment. This study includes 4 periods: Screening, open label, randomized withdrawal, and long-term treatment extension (LTE).

Conditions

Symptomatic Neurogenic Orthostatic Hypotension; MSA - Multiple System Atrophy

Outcome Measures

Primary Outcomes (1)

• Change in OHSA composite score at Week 8 during the double-blind RW period

  Score change from baseline on the composite of Questions 1 - 6 of the Orthostatic Hypotension Symptom Assessment (OHSA).

  8-week randomized withdrawal period (Week 12 to Week 20)

Secondary Outcomes (2)

• Change from baseline in OHDAS item 1 (activities that require standing for a short time) at Week 8 post randomization

  8-week randomized withdrawal period (Week 12 to Week 20)

• Change from baseline in OHDAS item 3 (activities that require walking for a short time) at Week 8 post randomization

  8-week randomized withdrawal period (Week 12 to Week 20)

Study Arms (3)

Ampreloxetine (Open Label)

ACTIVE COMPARATOR

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.

Drug: Ampreloxetine

Ampreloxetine (Randomized Withdrawal)

PLACEBO COMPARATOR

After completing the open label, participants are randomized to either ampreloxetine or placebo receiving a single, oral, daily dose of active drug or placebo for a further 8 weeks.

Drug: Ampreloxetine; Drug: Placebo

Long-Term Extension Period

ACTIVE COMPARATOR

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.

Drug: Ampreloxetine

Interventions

Ampreloxetine DRUG

Oral tablet, QD

Also known as: TD-9855

Ampreloxetine (Open Label); Ampreloxetine (Randomized Withdrawal); Long-Term Extension Period

Placebo DRUG

Oral tablet, QD

Ampreloxetine (Randomized Withdrawal)

Eligibility Criteria

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

You may qualify if:

• Participant is male or female and at least 30 years old.
• Participant 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).
• Participant has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) confirmed by the Enrollment Steering Committee (ESC).
• Participant must meet the diagnostic criteria of nOH, as demonstrated by a sustained reduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) within 3 min of standing as part of orthostatic standing test or being tilted up ≥60o from a supine position as determined by a tilt-table test.
• Participant must score ≤4 on UMSARS Part IV at Visit 1 (Screening).
• Participant must score at least a 4 on the OHSA item 1 at Visit 2 (Day 1).
• Participant must be willing to not take any prohibited medications during the study.
• If participant is female, the participant must not be pregnant, breastfeeding, or planning a pregnancy during the course of the study. A woman of childbearing potential must have a documented negative pregnancy test at screening.
• During the study and for 30 days after receiving the last dose of the study drug, females of childbearing potential or males capable of fathering children must agree to use highly effective birth control measures (failure rate \<1% when used consistently and correctly) or agree to abstain from sexual intercourse.
• Participant is willing and able to provide signed and dated written informed consent to -participate prior to initiation of any study related procedures.
• Participant is able to communicate well with the Investigator and clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.

You may not qualify if:

• Participant has a systemic illness known to produce autonomic neuropathy, including, but not limited to, amyloidosis and autoimmune neuropathies. Participant with diabetes mellitus (DM) will be evaluated on a case-by-case basis by the medical monitor and considered ineligible unless they meet all of the following criteria:
• Well controlled type-2 DM in treatment with only oral medications and diet
• HbA1C of ≤7.5% performed during screening or up to 12 weeks before screening
• No clinically evident peripheral neuropathy (e.g., normal sensory examination on peripheral extremities)
• No known retinopathy (e.g., annual ophthalmic exam is sufficient)
• No nephropathy (e.g., absence of albuminuria and GFR \>60).
• Participant has a known intolerance to other NRIs or SNRIs.
• Participant currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
• Participant has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half lives, whichever is longer, prior to Visit 2 (Day 1) or requires concomitant use until the Safety follow-up Visit.
• Participant has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to Visit 2 (Day 1).
• Midodrine and droxidopa (if applicable) must be tapered off and stopped at least 7 days prior to Visit 2 (Day 1).
• Participant 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).
• Participant has clinically unstable coronary artery disease or had a major cardiovascular event (e.g., myocardial infarction) in the past 6 months.
• Participant has significant uncontrolled cardiac arrhythmia, history of complete heart block, or significant QTc prolongation (≥450 msec for males and ≥470 msec for females).
• Participant has a new onset of a neurological event (i.e., seizures, confusion, altered levels of consciousness, etc.) in the past 6 months.

Sponsors & Collaborators

• Theravance Biopharma: lead

Study Sites (79)

Movement Disorders Center of Arizona

Scottsdale, Arizona, 85258, United States

Location

The Parkinson's and Movement Disorder Institute

Fountain Valley, California, 92708, United States

Location

UC San Diego Movement Disorder Center

La Jolla, California, 92037, United States

Location

David Geffen School of Medicine at UCLA

Los Angeles, California, 90095, United States

Location

Stanford Neuroscience Health Center

Palo Alto, California, 94304, United States

Location

Medstar Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Parkinson's Disease And Movement Disorders Center of Boca Raton

Boca Raton, Florida, 33486, United States

Location

SFM Clinical Research, LLC

Boca Raton, Florida, 33487, United States

Location

Aqualane Clinical Research

Naples, Florida, 34105, United States

Location

Neurostudies, Inc

Port Charlotte, Florida, 33952, United States

Location

University of South Florida Ataxia Research Center

Tampa, Florida, 33612, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

Hawaii Pacific Neuroscience

Honolulu, Hawaii, 96817, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Northshore University Health System

Glenview, Illinois, 60026-1339, United States

Location

University of Kansas Medical Center Research Institute, Inc.

Kansas City, Kansas, 66160, United States

Location

Brigham and Women's Hospital (Neuromuscular Division)

Boston, Massachusetts, 02115, United States

Location

Massachusetts Chan Medical School

Worcester, Massachusetts, 01655, United States

Location

Quest Research Institute

Farmington Hills, Michigan, 48334, United States

Location

NYU Langone Health NYU Dysautonomia Center

New York, New York, 10016, United States

Location

The Neurological Institute at Columbia University Medical Center

New York, New York, 10032, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, 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

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Movement Disorders and Autonomic Disorders Clinic; University of Utah

Salt Lake City, Utah, 84108, United States

Location

INEBA Instituto Neurociencias Buenos Aires

CABA, Buenos Aires F.D., C1192AAW, Argentina

Location

Instituto Fleni

CABA, Buenos Aires F.D., C1428AQK, Argentina

Location

Médico/Hospital de la Policía Federal Churruca Visca

CABA, Buenos Aires F.D., C1437JCP, Argentina

Location

Hospital General de Agudos Jose Maria Ramos Mejía

CABA, C1221ADC, Argentina

Location

Hospital Británico de Buenos Aires

CABA, C1280AEB, Argentina

Location

Fundación Scherbovsky

Mendoza, M5500, Argentina

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

The Alfred Hospital

Melbourne, Victoria, 3168, Australia

Location

Theravance Biopharma Investigative Site

Parkville, Victoria, 3050, Australia

Location

Medical University of Innsbruck

Innsbruck, A-6020, Austria

Location

Universitatsklinikum Tulln

Tulln, Austria

Location

Instituto de Neurologia de Curitiba S\C LTDA

Curitiba, Paraná, 81210-310, Brazil

Location

Hospital de Clínicas - Universidade Federal de Minas Gerais (HC - UFMG)

Belo Horizonte, 30130-100, Brazil

Location

Centro de Pesquisa Clínica (CPC) do Hospital das Clínicas de Porto Alegre (HCPA)

Porto Alegre, 90035-903, Brazil

Location

Hospital São Lucas - PUCRS

Porto Alegre, 90610-000, Brazil

Location

University of Calgary - Health Sciences Centre

Calgary, Alberta, T2N 4Z6, Canada

Location

Bispebjerg Hospital

Copenhagen, 2400-NV, Denmark

Location

Astra Clinic (Clinic4U)

Tallinn, 11315, Estonia

Location

Tartu University Hospital

Tartu, 30029, Estonia

Location

Hopital Caremeau

Nîmes, Occitanie, Cedex 9, France

Location

Centre Hospitalier Universitaire de Bordeaux Health

Bordeaux, 33076, France

Location

Centre d'Investigation Clinique Hôpital Pierre Paul Rique

Toulouse, 31059 Cedex, France

Location

Praxis Dr. Oehlwein, Outpatient Clinic

Gera, Thuringia, 07551, Germany

Location

Charité - Universitätsmedizin Berlin- Campus Mitte

Berlin, 10117, Germany

Location

Charite Universitaetsmedizin Berlin

Berlin, 12203, Germany

Location

Semmelweis Egyetem

Budapest, 1085, Hungary

Location

Theravance Biopharma Investigative Site

Tel Aviv, 64239, Israel

Location

IRCCS Istituto de Scienze Neurologiche di Bologna (ISNB)

Bologna, 40139, Italy

Location

Parkinson's Centre of Ospedale CTO

Milan, 20126, Italy

Location

Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Rome, 00133, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Rome, 00168, Italy

Location

AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno

Salerno, 84131, Italy

Location

Azienda Ospedaliera Santa Maria di Terni

Terni, I-05100, Italy

Location

Santa Chiara Hospital

Trento, 38122, Italy

Location

Pia Fond. Cardinale Giovanni Panico Azienda Ospedaliera

Tricase, 73039, Italy

Location

Auckland City Hospital

Grafton, Auckland, 1023, New Zealand

Location

Theravance Biopharma Investigative Site

Christchurch, 8011, New Zealand

Location

Neurocentrum-Miwomed

Gdansk, 80-207, Poland

Location

Neuro-Care Sp. z o.o. Sp. Komandytowa

Katowice, 40-749, Poland

Location

Krakowska Akademia Neurologii Sp.zo.o.

Krakow, 31-505, Poland

Location

Instytut Zdrowia dr Boczarska-Jedynak Sp. z o.o., Sp.k.

Oświęcim, 32-600, Poland

Location

CNS-Campus Neurologico Senior

Torres Vedras, 2560-280, Portugal

Location

University of Belgrade Neurology Clinic

Belgrade, 11000, Serbia

Location

Fundació Assistencial Mutua de Terrassa

Terrassa, Barcelona, 08222, Spain

Location

Hospital Germans Trias i Pujol, Department of Neurology

Barakaldo, Bizkaia, 48903, Spain

Location

Instituto Investigación Sanitaria Biocruces

Barakaldo, Bizkaia, 48903, Spain

Location

Hospital Universitario de La Princesa

Madrid, 28006, Spain

Location

Hospital Universitario Infante Sofia Paseo Europa

Madrid, 28702, Spain

Location

National Taiwan University Cancer Center

Taipei, Taiwan, 106, Taiwan

Location

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2GW, United Kingdom

Location

Barts Health

London, EC1M 6BQ, United Kingdom

Location

Autonomic Unit, National Hospital for Neurology & Neurosurgery

London, WC1N 3BG, United Kingdom

Location

Salford Royal Hospital

Salford, M6 8HD, United Kingdom

Location

MeSH Terms

Conditions

Shy-Drager Syndrome

Interventions

ampreloxetine

Condition Hierarchy (Ancestors)

Multiple System Atrophy; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Hypotension; Vascular Diseases; Cardiovascular Diseases

Study Design

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

Model Details: Open Label followed by Randomized Parallel Assignment

Study Record Dates

• First Submitted: January 13, 2023
• First Posted: January 25, 2023
• Study Start: June 27, 2023
• Primary Completion: January 1, 2026
• Study Completion (Estimated): January 1, 2028
• Last Updated: September 5, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); TW (1); CA (1); PT (1); GB (4); ES (5); IT (8); NZ (2); AU (3); AR (6); DK (1); HU (1); IL (1); US (26); DE (3); SE (1); BR (4); PL (4)