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

A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure

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

Study Overview

• Status: Terminated
• Conditions: Parkinson's Disease (PD); MSA; Symptomatic Neurogenic Orthostatic Hypotension; Pure Autonomic Failure (PAF)
• Intervention / Treatment: Drug: Placebo; Drug: ampreloxetine

Detailed Description

Phase 3, multi-center, randomized withdrawal study to evaluate the sustained benefit in efficacy and safety of ampreloxetine in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH. The study consists of 3 periods: (i) 16-week open-label (OL) treatment with ampreloxetine, (ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up (only for patients who do not enroll in Study 0171 (long-term extension safety study)).

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 02139
      • Concord Hospital, Neurosciences Department
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Clinical Trials Centre, Level 3 Monash Health Translational Precinct Building Monash Medical Centre
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital Neurology Department
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Perron Institute for Neurological and Translational Science
• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universitat Innsbruck, Abteilung fur Neurologie
  • Tulln, Austria, 3430
    • Universitatsklinikum Tulln Abteilung fur Neurologie
• Bulgaria
  • Sofia, Bulgaria, 1113
    • MHATNP Sv. Naum EAD Clinic of Neurological Diseases for Locomotor Disorders
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary Teaching Research and Wellness Building
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute & Hospital
• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital
  • Odense, Denmark, 5000
    • Odense Universitetshospital
• Estonia
  • Tallinn, Estonia, 10138
    • East Tallinn Central Hospital
  • Tallinn, Estonia, 11315
    • Astra Team Clinic
  • Tartu, Estonia, 50406
    • Tartu University Hospital
• France
  • Nîmes, France, 30029
    • CHU de Nîmes - Hôpital Carémeau
• Germany
  • Berlin, Germany, 13353
    • Charite - Campus Virchow-Klinikum, Klinik fur Neurologie
  • Berlin, Germany, 12203
    • Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin
  • Gera, Germany, 7551
    • Praxis Dr. Med. Christian Oehlwein
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem, Neurologiai Klinika
• Israel
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center, Beilinson campus
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
• Italy
  • Bologna, Italy, 40139
    • Universita di Bologna-Clinica Neurologica - Dipt di Scienze Neurologiche Ospedale Bellaria
  • Catania, Italy, 95125
    • Azienda Ospedaliera Universitaria Policlinico - Vittorio Emanuele (Presidio Gaspare Rodolico)
  • Chieti, Italy, 66100
    • Universita degli studi Gabriele D' Annunzio Chieti
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
  • Pisa, Italy, 56126
    • Azienda Ospedaliero-Universitaria Pisana- Ospedale S. Chiara, U.O. di Neurologia - Neurofisiopatologia
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento
  • Roma, Italy, 00133
    • Fondazione PTV - Policlinico Tor Vergata I U.0.C. Neurologia
  • Salerno, Italy, 84131
    • AOU San Giovanni di Dio e Ruggi d'Aragona
  • Terni, Italy, 05100
    • A.O. Santa Maria
• New Zealand
  • Christchurch, New Zealand, 8011
    • New Zealand Brain Research Institute
• Poland
  • Katowice, Poland, 40-588
    • Specjalistyczna Praktyka Lekarska, Prof. Grzegorz Opala
  • Kraków, Poland, 31-505
    • Krakowska Akademia Neurologii Sp. Zo.o. Centrum Neurologii Klinicznej
  • Oswiecim, Poland, 32-600
    • Instytut Zdrowia dr Boczarska-Jedynak
  • Siemianowice Śląskie, Poland, 41-100
    • NEURO-CARE Sp. z o.o. Sp. Komandytowa
  • Warszawa, Poland, 02-777
    • ETG Warszawa
  • Warszawa, Poland, 30-539
    • Specjalistyczne Gabinety Sp. z o.o.
• Portugal
  • Guimarães, Portugal, 4835-044
    • Hospital da Senhora da Oliveira Guimarães
  • Torres Vedras, Portugal, 2560-280
    • CNS-Campus Neurologico Senior
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660037
    • FSBI Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency
  • Novosibirsk, Russian Federation, 630054
    • State Budgetary Institution of Healthcare of Novosibirsk region City Clinical Hospital #34
  • Novosibirsk, Russian Federation, 630091
    • City Neurological Center Sibneiromed, LLC
  • Saint Petersburg, Russian Federation, 192019
    • FSBI National Medical Research Centre of psychiatry and neurology named after V.M. Bekhterev of the MOH of the Russian Federation
  • Saint Petersburg, Russian Federation, 197376
    • FSBI of Science Institute of Human Brain named after N .P. Bekhtereva of Russian Academy of Sciences
  • Sestroretsk
    • Saint Petersburg, Sestroretsk, Russian Federation, 197706
      • Saint Petersburg State Budgetary Institution of Healthcare City Hospital #40 of Kurortnyi Region
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Barcelona
    • Terrassa, Barcelona, Spain, 08221
      • Hospital Universitario Mutua de Terrasa
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Complejo Hospitalario de Navarra
  • Vizcaya
    • Bilbao, Vizcaya, Spain, 48903
      • Hospital de Cruces
• Ukraine
  • Kharkiv, Ukraine, 61172
    • Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council
  • Lviv, Ukraine, 79010
    • Communal noncommercial enterprise of Lviv Regional Council Lviv Regional Clinical Hospital
  • Vinnytsia, Ukraine, 21005
    • Communal Institution Acad. O.I. Yuschenko VRPsH Vinnytsia M.I. Pyrogov NMU Ch of ND with the Course of Neurosurgery
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • London, United Kingdom, W1G 9JF
    • Re:Cognition Health Ltd
  • London, United Kingdom, EC1M 6BQ
    • Clinical Research Centre, William Harvey Heart Centre
  • London, United Kingdom, WC1N 3BG
    • The National Hospital for Neurology & Neurosurgery
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital NHS Trust
    • Plymouth, Devon, United Kingdom, PL6 8BT
      • Cognition Health Unit 2
  • Greater Manchester
    • Salford, Greater Manchester, United Kingdom, M6 8HD
      • Salford Royal NHS Foundation Trust
• United States
  • Arizona
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
  • California
    • La Jolla, California, United States, 92307
      • UC San Diego Movement Disorder Center
    • Palo Alto, California, United States, 94304
      • Stanford Neuroscience Health Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Colorado Springs Neurological Associates, PC
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center
    • Boca Raton, Florida, United States, 33487
      • SFM Clinical Research, LLC
    • Port Charlotte, Florida, United States, 33952
      • Neurostudies, Inc
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Glenview, Illinois, United States, 60026
      • NorthShore University Health System
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center Research Institute, Inc.
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10016
      • New York University Langone Health
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Health Sciences
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center (UCGNI)
    • Columbus, Ohio, United States, 43210
      • Ohio State University - Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Virginia
    • McLean, Virginia, United States, 22101
      • Georgetown University Hospital
  • Washington
    • Spokane, Washington, United States, 99202
      • Inland Northwest Research

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria (For 0169 Completers Group):

• 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.

Inclusion Criteria (For De Novo Group):

• 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.

Exclusion Criteria (For 0169 Completers Group):

• 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.

Exclusion Criteria (For De Novo Group):

• 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.
• Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
• 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 finding (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/1.73 m2, 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 Columbia Suicide Severity Rating Scale (C-SSRS)(Baseline/Screening Version). Subject should be assessed by the rater for risk of suicide and the subject's appropriateness for inclusion in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ampreloxetine (Open Label (OL)); Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.	Drug: ampreloxetine; Oral tablet, QD (Daily); Other Names: TD-9855
Experimental: ampreloxetine; After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.	Drug: ampreloxetine; Oral tablet, QD (Daily); Other Names: TD-9855
Placebo Comparator: Placebo; After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.	Drug: Placebo; Oral tablet, QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in OHSA#1 at Week 6 post randomization at Week 6 post randomization.	Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout.	6-week randomized withdrawal period (Week 16 to Week 22)
Change from baseline in OHSA composite score at Week 6 post randomization	Orthostatic Hypotension Symptom Assessment (OHSA) is an assessment of the severity of symptoms from low blood pressure.	6-week randomized withdrawal period (Week 16 to Week 22)
Change from baseline in OHDAS composite score at Week 6 post randomization	Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life. OHDAS is a 4 item assessment that uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.	6-week randomized withdrawal period (Week 16 to Week 22)
Change from baseline in PGI-S at Week 6 post randomization	Score change from baseline on Patient Global Impression of Severity (PGI-S). PGI-S assesses patient's impression of disease severity.	6-week randomized withdrawal period (Week 16 to Week 22)
Change from baseline in percent of time spent in standing position as measured by a wearable device at Week 6 post randomization	A wearable device, such as an activity monitor, that provides date- and time-stamped activity information will be used to collect raw motion data to measure the time spent in supine, sitting, and standing positions.	6-week randomized withdrawal period (Week 16 to Week 22)
Change from baseline in average number of steps taken as measured by a wearable device at Week 6 post randomization	A wearable device, such as an activity monitor, that provides date- and time-stamped activity information will be used to collect raw motion data to measure the time spent in supine, sitting, and standing positions.	6-week randomized withdrawal period (Week 16 to Week 22)

Collaborators and Investigators

• Sponsor: Theravance Biopharma

Publications and helpful links

Helpful Links

• Click on the link to see if you qualify to participate

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2019
• Primary Completion (Actual): November 10, 2021
• Study Completion (Actual): November 10, 2021

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 31, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Actual): January 20, 2023
• Last Update Submitted That Met QC Criteria: December 29, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: MSA; orthostatic hypotension; norepinephrine; Parkinson's disease; PD; dizziness; hypotension; fainting; Parkinsonism; PAF; Symptomatic Neurogenic Orthostatic Hypotension; symptomatic nOH; pure autonomic failure; ampreloxetine; low blood pressure; blacking out; lightheadedness; TD-9855; Neurogenic Orthostatic Hypotension; nOH; 0145; 145; TD9855; multiple symptom atrophy; OH; REDWOOD; 170; 0170
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Autonomic Nervous System Diseases; Primary Dysautonomias; Orthostatic Intolerance; Parkinson Disease; Hypotension; Hypotension, Orthostatic; Pure Autonomic Failure
• Other Study ID Numbers: 0170; 2018-003941-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No