Clinical trial NCT03829657: Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
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
Lead sponsor: Theravance Biopharma
Sponsor class: INDUSTRY
First posted: 2019-02-04
Enrollment: 203
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open Label Extension followed by Randomized Parallel Assignment
Primary purpose: TREATMENT

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

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)).

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period
timeFrame: 6-week randomized withdrawal period (Week 16 to Week 22)
Secondary outcomes:
Other outcomes:
Locations:
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Movement Disorder Center
state: California
city: Palo Alto
country: United States
facility: Stanford Neuroscience Health Center
state: California
city: Colorado Springs
country: United States
facility: Colorado Springs Neurological Associates, PC
state: Colorado
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center
state: Florida
city: Boca Raton
country: United States
facility: SFM Clinical Research, LLC
state: Florida
city: Port Charlotte
country: United States
facility: Neurostudies, Inc
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Glenview
country: United States
facility: NorthShore University Health System
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Health Sciences
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center (UCGNI)
state: Ohio
city: Columbus
country: United States
facility: Ohio State University - Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: McLean
country: United States
facility: Georgetown University Hospital
state: Virginia
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Concord
country: Australia
facility: Concord Hospital, Neurosciences Department
state: New South Wales
city: Clayton
country: Australia
facility: Clinical Trials Centre, Level 3 Monash Health Translational Precinct Building Monash Medical Centre
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital Neurology Department
state: Victoria
city: Nedlands
country: Australia
facility: Perron Institute for Neurological and Translational Science
state: Western Australia
city: Innsbruck
country: Austria
facility: Medizinische Universitat Innsbruck, Abteilung fur Neurologie
city: Tulln
country: Austria
facility: Universitatsklinikum Tulln Abteilung fur Neurologie
city: Sofia
country: Bulgaria
facility: MHATNP Sv. Naum EAD Clinic of Neurological Diseases for Locomotor Disorders
city: Calgary
country: Canada
facility: University of Calgary Teaching Research and Wellness Building
state: Alberta
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute & Hospital
state: Quebec
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital
city: Tallinn
country: Estonia
facility: Astra Team Clinic
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Nîmes
country: France
facility: CHU de Nîmes - Hôpital Caremeau
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum, Klinik fur Neurologie
city: Gera
country: Germany
facility: Praxis Dr. med. Christian Oehlwein
city: Budapest
country: Hungary
facility: Semmelweis Egyetem, Neurologiai Klinika
city: Petah Tikva
country: Israel
facility: Rabin Medical Center, Beilinson Campus
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Bologna
country: Italy
facility: Universita di Bologna-Clinica Neurologica - Dipt di Scienze Neurologiche Ospedale Bellaria
city: Catania
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico - Vittorio Emanuele (Presidio Gaspare Rodolico)
city: Chieti
country: Italy
facility: Universita degli studi Gabriele D' Annunzio Chieti
city: Milano
country: Italy
facility: Fondazione IRCCS CA Granda Ospedale Maggiore Policlinico
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana- Ospedale S. Chiara, U.O. di Neurologia - Neurofisiopatologia
city: Roma
country: Italy
facility: Fondazione PTV - Policlinico Tor Vergata I U.0.C. Neurologia
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento
city: Salerno
country: Italy
facility: AOU San Giovanni di Dio e Ruggi d'Aragona
city: Terni
country: Italy
facility: A.O. Santa Maria
city: Christchurch
country: New Zealand
facility: New Zealand Brain Research Institute
city: Katowice
country: Poland
facility: Specjalistyczna Praktyka Lekarska, Prof. Grzegorz Opala
city: Kraków
country: Poland
facility: Krakowska Akademia Neurologii Sp. Zo.o. Centrum Neurologii Klinicznej
city: Oswiecim
country: Poland
facility: Instytut Zdrowia dr Boczarska-Jedynak
city: Siemianowice Śląskie
country: Poland
facility: NEURO-CARE Sp. z o.o. Sp. Komandytowa
city: Warszawa
country: Poland
facility: ETG Warszawa
city: Warszawa
country: Poland
facility: Specjalistyczne Gabinety sp. z o.o.
city: Guimarães
country: Portugal
facility: Hospital da Senhora da Oliveira Guimarães
city: Torres Vedras
country: Portugal
facility: CNS-Campus Neurologico Senior
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Budgetary Institution of Healthcare City Hospital #40 of Kurortnyi Region
state: Sestroretsk
city: Krasnoyarsk
country: Russian Federation
facility: FSBI Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency
city: Novosibirsk
country: Russian Federation
facility: State Budgetary Institution of Healthcare of Novosibirsk region City Clinical Hospital #34
city: Novosibirsk
country: Russian Federation
facility: City Neurological Center Sibneiromed, LLC
city: Saint Petersburg
country: Russian Federation
facility: FSBI National Medical Research Centre of psychiatry and neurology named after V.M. Bekhterev of the MOH of the Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: FSBI of Science Institute of Human Brain named after N .P. Bekhtereva of Russian Academy of Sciences
city: Terrassa
country: Spain
facility: Hospital Universitario Mutua de Terrasa
state: Barcelona
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
state: Navarra
city: Bilbao
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Kharkiv
country: Ukraine
facility: Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council
city: Lviv
country: Ukraine
facility: Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital
city: Vinnytsia
country: Ukraine
facility: Communal Institution Acad. O.I. Yuschenko VRPsH Vinnytsia M.I. Pyrogov NMU Ch of ND with the Course of Neurosurgery
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital NHS Trust
state: Devon
city: Plymouth
country: United Kingdom
facility: Cognition Health Unit 2
state: Devon
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
state: Greater Manchester
city: London
country: United Kingdom
facility: Clinical Research Centre, William Harvey Heart Centre
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Re:Cognition Health Ltd
city: London
country: United Kingdom
facility: The National Hospital for Neurology & Neurosurgery
Study officials:
affiliation: Theravance Biopharma
name: Medical Monitor
role: STUDY_DIRECTOR
References: