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

Parkinson's Disease (PD) Clinical Trial

— REDWOOD  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03829657
• Other study ID #: 0170
• Secondary ID: 2018-003941-41
• Status: Terminated
• Phase: Phase 3
• Start date: February 22, 2019
• Est. completion date: November 10, 2021

Study information

• Verified date: December 2022
• Source: Theravance Biopharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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)).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 203
• Est. completion date: November 10, 2021
• Est. primary completion date: November 10, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypotension
• Hypotension, Orthostatic
• MSA
• Parkinson Disease
• Parkinson's Disease (PD)
• Pure Autonomic Failure
• Symptomatic Neurogenic Orthostatic Hypotension

Intervention

Drug:
• ampreloxetine
Oral tablet, QD (Daily)
• Placebo
Oral tablet, QD

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Theravance Biopharma

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  Canada,  Denmark,  Estonia,  France,  Germany,  Hungary,  Israel,  Italy,  New Zealand,  Poland,  Portugal,  Russian Federation,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)

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