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Symptomatic Neurogenic Orthostatic HypotensionPhase 3CYPRESSNCT05696717

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

A Phase 3 study testing Ampreloxetine in people with Symptomatic Neurogenic Orthostatic Hypotension and MSA - Multiple System Atrophy, run by Theravance Biopharma at 79 sites in 20 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 30 years and older
What is being tested?
Ampreloxetine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
102 participants
Where
79 sitesin 20 countries
Study dates
27 Jun 2023to Jan 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).
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  • 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.

Who cannot join

  • 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).
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  • 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.
  • Participant has used any monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 2 (Day 1).
  • Participant 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 participant.
  • Participant has a Montreal Cognitive Assessment (MoCA) <21.
  • Participant is unable or unwilling to complete all protocol specified procedures including questionnaires.
  • Participant has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
  • Participant has had any malignant disease, other than carcinoma in situ of the cervix or basal cell carcinoma, within the past 2 years prior to Screening.
  • Participant has a known gastrointestinal (GI) condition, which in the Investigator's judgment, may affect the absorption of study medication (e.g., ulcerative colitis, gastric bypass).
  • Participant has psychiatric, neurological, or behavioral disorders that may interfere with the cognitive ability of the participant to give informed consent, understand and comply with study procedures, or interfere with the conduct of the study.
  • Participant is currently receiving any investigational drug or has received an investigational drug within 30 days of dosing. An investigational drug is defined as a drug that is not approved by a regulatory agency (e.g., Food and Drug Administration [FDA]).
  • Participant has a clinically significant abnormal laboratory finding(s) (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥3.0 x upper limit of normal [ULN]; blood bilirubin [total] ≥3.0 x ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could interfere with safety of the participant).
  • Participant has demonstrated lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Baseline/Screening Version). Participant should be assessed by the rater for risk of suicide and the participant's appropriateness for inclusion in the study.
  • Participant has a concurrent disease or condition (e.g., COVID-19), or recent surgery, that in the opinion of the Investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or absorption of the study drug.
  • Participant has known hypersensitivity to ampreloxetine (ampreloxetine hydrochloride), or any excipients in the formulation.
  • Major surgery (i.e., procedures involving higher risk for infection and extended recovery period, such as, joint replacement, gastric bypass, open heart surgery, organ transplant, etc.) occurring less than 4 weeks prior to enrollment.

Trial locations and contacts

79 sites in 20 countries.

79 sites in 20 countries

United States26 sites

  • Emory University

    Atlanta, Georgia, 30329

  • Parkinson's Disease And Movement Disorders Center of Boca Raton

    Boca Raton, Florida, 33486

  • SFM Clinical Research, LLC

    Boca Raton, Florida, 33487

  • Brigham and Women's Hospital (Neuromuscular Division)

    Boston, Massachusetts, 02115

  • Rush University Medical Center

    Chicago, Illinois, 60612

  • University of Cincinnati Medical Center

    Cincinnati, Ohio, 45219

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • Quest Research Institute

    Farmington Hills, Michigan, 48334

  • The Parkinson's and Movement Disorder Institute

    Fountain Valley, California, 92708

  • Northshore University Health System

    Glenview, Illinois, 60026-1339

  • Hawaii Pacific Neuroscience

    Honolulu, Hawaii, 96817

  • Baylor College of Medicine

    Houston, Texas, 77030

  • University of Kansas Medical Center Research Institute, Inc.

    Kansas City, Kansas, 66160

  • UC San Diego Movement Disorder Center

    La Jolla, California, 92037

  • David Geffen School of Medicine at UCLA

    Los Angeles, California, 90095

  • Aqualane Clinical Research

    Naples, Florida, 34105

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

  • NYU Langone Health NYU Dysautonomia Center

    New York, New York, 10016

  • The Neurological Institute at Columbia University Medical Center

    New York, New York, 10032

  • Stanford Neuroscience Health Center

    Palo Alto, California, 94304

  • Neurostudies, Inc

    Port Charlotte, Florida, 33952

  • Movement Disorders and Autonomic Disorders Clinic; University of Utah

    Salt Lake City, Utah, 84108

  • Movement Disorders Center of Arizona

    Scottsdale, Arizona, 85258

  • University of South Florida Ataxia Research Center

    Tampa, Florida, 33612

  • Medstar Georgetown University Hospital

    Washington D.C., District of Columbia, 20007

  • Massachusetts Chan Medical School

    Worcester, Massachusetts, 01655

Other trials in United States

Italy8 sites

  • IRCCS Istituto de Scienze Neurologiche di Bologna (ISNB)

    Bologna, 40139

  • Parkinson's Centre of Ospedale CTO

    Milan, 20126

  • Azienda Ospedaliera Universitaria Policlinico Tor Vergata

    Rome, 00133

  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS

    Rome, 00168

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

    Salerno, 84131

  • Azienda Ospedaliera Santa Maria di Terni

    Terni, I-05100

  • Santa Chiara Hospital

    Trento, 38122

  • Pia Fond. Cardinale Giovanni Panico Azienda Ospedaliera

    Tricase, 73039

Other trials in Italy

Argentina6 sites

  • INEBA Instituto Neurociencias Buenos Aires

    CABA, Buenos Aires F.D., C1192AAW

  • Instituto Fleni

    CABA, Buenos Aires F.D., C1428AQK

  • Médico/Hospital de la Policía Federal Churruca Visca

    CABA, Buenos Aires F.D., C1437JCP

  • Hospital General de Agudos Jose Maria Ramos Mejía

    CABA, C1221ADC

  • Hospital Británico de Buenos Aires

    CABA, C1280AEB

  • Fundación Scherbovsky

    Mendoza, M5500

Other trials in Argentina

Spain5 sites

  • Hospital Germans Trias i Pujol, Department of Neurology

    Barakaldo, Bizkaia, 48903

  • Instituto Investigación Sanitaria Biocruces

    Barakaldo, Bizkaia, 48903

  • Hospital Universitario de La Princesa

    Madrid, 28006

  • Hospital Universitario Infante Sofia Paseo Europa

    Madrid, 28702

  • Fundació Assistencial Mutua de Terrassa

    Terrassa, Barcelona, 08222

Other trials in Spain

Brazil4 sites

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

    Belo Horizonte, 30130-100

  • Instituto de Neurologia de Curitiba S\C LTDA

    Curitiba, Paraná, 81210-310

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

    Porto Alegre, 90035-903

  • Hospital São Lucas - PUCRS

    Porto Alegre, 90610-000

Other trials in Brazil

Poland4 sites

  • Neurocentrum-Miwomed

    Gdansk, 80-207

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

    Katowice, 40-749

  • Krakowska Akademia Neurologii Sp.zo.o.

    Krakow, 31-505

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

    Oświęcim, 32-600

Other trials in Poland

United Kingdom4 sites

  • University Hospitals Birmingham NHS Foundation Trust

    Birmingham, B15 2GW

  • Barts Health

    London, EC1M 6BQ

  • Autonomic Unit, National Hospital for Neurology & Neurosurgery

    London, WC1N 3BG

  • Salford Royal Hospital

    Salford, M6 8HD

Other trials in United Kingdom

Australia3 sites

  • Monash Health

    Clayton, Victoria, 3168

  • The Alfred Hospital

    Melbourne, Victoria, 3168

  • Theravance Biopharma Investigative Site

    Parkville, Victoria, 3050

Other trials in Australia

France3 sites

  • Centre Hospitalier Universitaire de Bordeaux Health

    Bordeaux, 33076

  • Hopital Caremeau

    Nîmes, Occitanie, Cedex 9

  • Centre d'Investigation Clinique Hôpital Pierre Paul Rique

    Toulouse, 31059 Cedex

Other trials in France

Germany3 sites

  • Charité - Universitätsmedizin Berlin- Campus Mitte

    Berlin, 10117

  • Charite Universitaetsmedizin Berlin

    Berlin, 12203

  • Praxis Dr. Oehlwein, Outpatient Clinic

    Gera, Thuringia, 07551

Other trials in Germany

Austria2 sites

  • Medical University of Innsbruck

    Innsbruck, A-6020

  • Universitatsklinikum Tulln

    Tulln

Other trials in Austria

Estonia2 sites

  • Astra Clinic (Clinic4U)

    Tallinn, 11315

  • Tartu University Hospital

    Tartu, 30029

Other trials in Estonia

New Zealand2 sites

  • Theravance Biopharma Investigative Site

    Christchurch, 8011

  • Auckland City Hospital

    Grafton, Auckland, 1023

Other trials in New Zealand

Canada1 site

  • University of Calgary - Health Sciences Centre

    Calgary, Alberta, T2N 4Z6

Other trials in Canada

Denmark1 site

  • Bispebjerg Hospital

    Copenhagen, 2400-NV

Other trials in Denmark

Hungary1 site

  • Semmelweis Egyetem

    Budapest, 1085

Other trials in Hungary

Israel1 site

  • Theravance Biopharma Investigative Site

    Tel Aviv, 64239

Other trials in Israel

Portugal1 site

  • CNS-Campus Neurologico Senior

    Torres Vedras, 2560-280

Other trials in Portugal

Serbia1 site

  • University of Belgrade Neurology Clinic

    Belgrade, 11000

Other trials in Serbia

Taiwan1 site

  • National Taiwan University Cancer Center

    Taipei, Taiwan, 106

Other trials in Taiwan

About this study

Official title: A Phase 3, Multi-center, Randomized Withdrawal and Long Term Extension Study of Ampreloxetine for the Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Participants With Multiple System Atrophy

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).

Being tested
Ampreloxetine, Placebo
Medical subject headings
Shy-Drager Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AmpreloxetineDrug

    Also called TD-9855

    Oral tablet, QD

  • PlaceboDrug

    Oral tablet, QD

Study groups in NCT05696717
Study groupRoleWhat they receive
Ampreloxetine (Open Label)Active comparatorParticipants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.
Receives: Drug: Ampreloxetine
Ampreloxetine (Randomized Withdrawal)Placebo comparatorAfter 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.
Receives: Drug: Ampreloxetine; Drug: Placebo
Long-Term Extension PeriodActive comparatorParticipants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.
Receives: Drug: Ampreloxetine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

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

Secondary outcomes (2)

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

    Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.

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

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

    Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jan 2023
  2. Study start27 Jun 2023
  3. Primary completionJan 2026 (estimated)
  4. Study completionJan 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Open Label followed by Randomized Parallel Assignment
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
102 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05696717
Sponsor's protocol ID
2022-003903-14
Acronym
CYPRESS
Status last verified
Nov 2024
First submitted
13 Jan 2023
Last updated
5 Sep 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ampreloxetine in people with Symptomatic Neurogenic Orthostatic Hypotension and MSA - Multiple System Atrophy, run by Theravance Biopharma at 79 sites in 20 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 5 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 79 sites in United States, Italy, Argentina, Spain, Brazil and 15 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in OHSA composite score at Week 8 during the double-blind RW period (time frame: 8-week randomized withdrawal period (Week 12 to Week 20)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05696717.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Sep 2025.

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