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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: MSA - Multiple System Atrophy; Symptomatic Neurogenic Orthostatic Hypotension
• Intervention / Treatment: Drug: Placebo; Drug: Ampreloxetine

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • CABA, Argentina, C1221ADC
    • Hospital General de Agudos José Maria Ramos Mejía
  • CABA, Argentina, C1280AEB
    • Hospital Britanico de Buenos Aires
  • Mendoza, Argentina, M5500
    • Fundacion Scherbovsky
  • Buenos Aires F.D.
    • CABA, Buenos Aires F.D., Argentina, C1192AAW
      • INEBA Instituto Neurociencias Buenos Aires
    • CABA, Buenos Aires F.D., Argentina, C1428AQK
      • Instituto Fleni
    • CABA, Buenos Aires F.D., Argentina, C1437JCP
      • Médico/Hospital de la Policía Federal Churruca Visca
• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Melbourne, Victoria, Australia, 3168
      • The Alfred Hospital
    • Parkville, Victoria, Australia, 3050
      • Theravance Biopharma Investigative Site
• Austria
  • Innsbruck, Austria, A-6020
    • Medical University of Innsbruck
  • Tulln, Austria
    • Universitätsklinikum Tulln
• Brazil
  • Belo Horizonte, Brazil, 30130-100
    • Hospital de Clínicas - Universidade Federal de Minas Gerais (HC - UFMG)
  • Porto Alegre, Brazil, 90610-000
    • Hospital Sao Lucas - PUCRS
  • Porto Alegre, Brazil, 90035-903
    • Centro de Pesquisa Clínica (CPC) do Hospital das Clínicas de Porto Alegre (HCPA)
  • Paraná
    • Curitiba, Paraná, Brazil, 81210-310
      • Instituto de Neurologia de Curitiba S\C LTDA
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary - Health Sciences Centre
• Denmark
  • Copenhagen, Denmark, 2400-NV
    • Bispebjerg Hospital
• Estonia
  • Tallinn, Estonia, 11315
    • Astra Clinic (Clinic4U)
  • Tartu, Estonia, 30029
    • Tartu University Hospital
• France
  • Bordeaux, France, 33076
    • Centre Hospitalier Universitaire de Bordeaux Health
  • Toulouse, France, 31059 Cedex
    • Centre d'Investigation Clinique Hôpital Pierre Paul Rique
  • Occitanie
    • Nîmes, Occitanie, France, Cedex 9
      • Hopital Caremeau
• Germany
  • Berlin, Germany, 12203
    • Charite Universitaetsmedizin Berlin
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin- Campus Mitte
  • Thuringia
    • Gera, Thuringia, Germany, 07551
      • Praxis Dr. Oehlwein, Outpatient Clinic
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis Egyetem
• Israel
  • Tel Aviv, Israel, 64239
    • Theravance Biopharma Investigative Site
• Italy
  • Bologna, Italy, 40139
    • IRCCS Istituto de Scienze Neurologiche di Bologna (ISNB)
  • Milan, Italy, 20126
    • Parkinson's Centre of Ospedale CTO
  • Rome, Italy, 00133
    • Azienda Ospedaliera Universitaria Policlinico Tor Vergata
  • Rome, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Salerno, Italy, 84131
    • AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno
  • Terni, Italy, I-05100
    • Azienda Ospedaliera Santa Maria di Terni
  • Trento, Italy, 38122
    • Santa Chiara Hospital
  • Tricase, Italy, 73039
    • Pia Fond. Cardinale Giovanni Panico Azienda Ospedaliera
• New Zealand
  • Christchurch, New Zealand, 8011
    • Theravance Biopharma Investigative Site
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital
• Poland
  • Gdansk, Poland, 80-207
    • Neurocentrum-Miwomed
  • Katowice, Poland, 40-749
    • NEURO-CARE Sp. z o.o. Sp. Komandytowa
  • Krakow, Poland, 31-505
    • Krakowska Akademia Neurologii Sp.zo.o.
  • Oświęcim, Poland, 32-600
    • Instytut Zdrowia dr Boczarska-Jedynak Sp. z o.o., Sp.k.
• Portugal
  • Torres Vedras, Portugal, 2560-280
    • CNS-Campus Neurologico Senior
• Serbia
  • Belgrade, Serbia, 11000
    • University of Belgrade Neurology Clinic
• Spain
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Madrid, Spain, 28702
    • Hospital Universitario Infante Sofia Paseo Europa
  • Barcelona
    • Terrassa, Barcelona, Spain, 08222
      • Fundacio Assistencial Mutua de Terrassa
  • Bizkaia
    • Barakaldo, Bizkaia, Spain, 48903
      • Hospital Germans Trias i Pujol, Department of Neurology
    • Barakaldo, Bizkaia, Spain, 48903
      • Instituto Investigación Sanitaria Biocruces
• Taiwan
  • Taiwan
    • Taipei, Taiwan, Taiwan, 106
      • National Taiwan University Cancer Center
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • University Hospitals Birmingham NHS Foundation Trust
  • London, United Kingdom, EC1M 6BQ
    • Barts Health
  • London, United Kingdom, WC1N 3BG
    • Autonomic Unit, National Hospital for Neurology & Neurosurgery
  • Salford, United Kingdom, M6 8HD
    • Salford Royal Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Movement Disorders Center of Arizona
  • California
    • Fountain Valley, California, United States, 92708
      • The Parkinson's and Movement Disorder Institute
    • La Jolla, California, United States, 92037
      • UC San Diego Movement Disorder Center
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
    • Palo Alto, California, United States, 94304
      • Stanford Neuroscience Health Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center of Boca Raton
    • Boca Raton, Florida, United States, 33487
      • SFM Clinical Research, LLC
    • Naples, Florida, United States, 34105
      • Aqualane Clinical Research
    • Port Charlotte, Florida, United States, 33952
      • Neurostudies, Inc
    • Tampa, Florida, United States, 33612
      • University of South Florida Ataxia Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Pacific Neuroscience
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Glenview, Illinois, United States, 60026-1339
      • Northshore University Health System
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center Research Institute, Inc.
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital (Neuromuscular Division)
    • Worcester, Massachusetts, United States, 01655
      • Massachusetts Chan Medical School
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • QUEST Research Institute
  • New York
    • New York, New York, United States, 10032
      • The Neurological Institute at Columbia University Medical Center
    • New York, New York, United States, 10016
      • NYU Langone Health NYU Dysautonomia Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Movement Disorders and Autonomic Disorders Clinic; University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ampreloxetine (Open Label); Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.	Drug: Ampreloxetine; Oral tablet, QD; Other Names: TD-9855
Placebo Comparator: Ampreloxetine (Randomized Withdrawal); 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: Placebo; Oral tablet, QD; Drug: Ampreloxetine; Oral tablet, QD; Other Names: TD-9855
Active Comparator: Long-Term Extension Period; Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.	Drug: Ampreloxetine; Oral tablet, QD; Other Names: TD-9855

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.	8-week randomized withdrawal period (Week 12 to Week 20)

Collaborators and Investigators

• Sponsor: Theravance Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2023
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: January 13, 2023
• First Submitted That Met QC Criteria: January 13, 2023
• First Posted (Actual): January 25, 2023

Study Record Updates

• Last Update Posted (Estimated): September 5, 2025
• Last Update Submitted That Met QC Criteria: August 29, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Basal Ganglia Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Multiple System Atrophy; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs; ampreloxetine
• Other Study ID Numbers: 2022-003903-14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No