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

NCT ID: NCT03829657

Last Updated: 2023-01-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 203 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-22
• Study Completion Date: 2021-11-10

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)).

Conditions

Symptomatic Neurogenic Orthostatic Hypotension; MSA; Parkinson's Disease (PD); Pure Autonomic Failure (PAF)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

ampreloxetine (Open Label (OL))

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.

Group Type: EXPERIMENTAL

ampreloxetine

Intervention Type: DRUG

Oral tablet, QD (Daily)

ampreloxetine

After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.

Group Type: EXPERIMENTAL

ampreloxetine

Intervention Type: DRUG

Oral tablet, QD (Daily)

Placebo

After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral tablet, QD

Interventions

ampreloxetine

Oral tablet, QD (Daily)

Intervention Type: DRUG

Placebo

Oral tablet, QD

Intervention Type: DRUG

Other Intervention Names

TD-9855

Eligibility Criteria

Inclusion Criteria

• 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.

• 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

• 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.

• 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.

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Theravance Biopharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Theravance Biopharma

Locations

Banner Sun Health Research Institute

Sun City, Arizona, United States

UC San Diego Movement Disorder Center

La Jolla, California, United States

Stanford Neuroscience Health Center

Palo Alto, California, United States

Colorado Springs Neurological Associates, PC

Colorado Springs, Colorado, United States

Parkinson's Disease and Movement Disorders Center

Boca Raton, Florida, United States

SFM Clinical Research, LLC

Boca Raton, Florida, United States

Neurostudies, Inc

Port Charlotte, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

NorthShore University Health System

Glenview, Illinois, United States

University of Kansas Medical Center Research Institute, Inc.

Kansas City, Kansas, United States

Mayo Clinic

Rochester, Minnesota, United States

New York University Langone Health

New York, New York, United States

Wake Forest University Baptist Health Sciences

Winston-Salem, North Carolina, United States

University of Cincinnati Medical Center (UCGNI)

Cincinnati, Ohio, United States

Ohio State University - Wexner Medical Center

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Georgetown University Hospital

McLean, Virginia, United States

Inland Northwest Research

Spokane, Washington, United States

Concord Hospital, Neurosciences Department

Concord, New South Wales, Australia

Clinical Trials Centre, Level 3 Monash Health Translational Precinct Building Monash Medical Centre

Clayton, Victoria, Australia

The Royal Melbourne Hospital Neurology Department

Parkville, Victoria, Australia

Perron Institute for Neurological and Translational Science

Nedlands, Western Australia, Australia

Medizinische Universitat Innsbruck, Abteilung fur Neurologie

Innsbruck, , Austria

Universitatsklinikum Tulln Abteilung fur Neurologie

Tulln, , Austria

MHATNP Sv. Naum EAD Clinic of Neurological Diseases for Locomotor Disorders

Sofia, , Bulgaria

University of Calgary Teaching Research and Wellness Building

Calgary, Alberta, Canada

Toronto Western Hospital

Toronto, Ontario, Canada

Montreal Neurological Institute & Hospital

Montreal, Quebec, Canada

Bispebjerg Hospital

Copenhagen, , Denmark

Odense Universitetshospital

Odense, , Denmark

East Tallinn Central Hospital

Tallinn, , Estonia

Astra Team Clinic

Tallinn, , Estonia

Tartu University Hospital

Tartu, , Estonia

CHU de Nîmes - Hôpital Caremeau

Nîmes, , France

Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin

Berlin, , Germany

Charite - Campus Virchow-Klinikum, Klinik fur Neurologie

Berlin, , Germany

Praxis Dr. med. Christian Oehlwein

Gera, , Germany

Semmelweis Egyetem, Neurologiai Klinika

Budapest, , Hungary

Rabin Medical Center, Beilinson Campus

Petah Tikva, , Israel

Kaplan Medical Center

Rehovot, , Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

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

Milan, , Italy

Azienda Ospedaliero-Universitaria Pisana- Ospedale S. Chiara, U.O. di Neurologia - Neurofisiopatologia

Pisa, , Italy

Fondazione PTV - Policlinico Tor Vergata I U.0.C. Neurologia

Roma, , Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento

Roma, , Italy

AOU San Giovanni di Dio e Ruggi d'Aragona

Salerno, , Italy

A.O. Santa Maria

Terni, , Italy

New Zealand Brain Research Institute

Christchurch, , New Zealand

Specjalistyczna Praktyka Lekarska, Prof. Grzegorz Opala

Katowice, , Poland

Krakowska Akademia Neurologii Sp. Zo.o. Centrum Neurologii Klinicznej

Krakow, , Poland

Instytut Zdrowia dr Boczarska-Jedynak

Oświęcim, , Poland

NEURO-CARE Sp. z o.o. Sp. Komandytowa

Siemianowice Śląskie, , Poland

ETG Warszawa

Warsaw, , Poland

Specjalistyczne Gabinety sp. z o.o.

Warsaw, , Poland

Hospital da Senhora da Oliveira Guimarães

Guimarães, , Portugal

CNS-Campus Neurologico Senior

Torres Vedras, , Portugal

Saint Petersburg State Budgetary Institution of Healthcare City Hospital #40 of Kurortnyi Region

Saint Petersburg, Sestroretsk, Russia

FSBI Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency

Krasnoyarsk, , Russia

State Budgetary Institution of Healthcare of Novosibirsk region City Clinical Hospital #34

Novosibirsk, , Russia

City Neurological Center Sibneiromed, LLC

Novosibirsk, , Russia

FSBI National Medical Research Centre of psychiatry and neurology named after V.M. Bekhterev of the MOH of the Russian Federation

Saint Petersburg, , Russia

FSBI of Science Institute of Human Brain named after N .P. Bekhtereva of Russian Academy of Sciences

Saint Petersburg, , Russia

Hospital Universitario Mutua de Terrasa

Terrassa, Barcelona, Spain

Complejo Hospitalario de Navarra

Pamplona, Navarre, Spain

Hospital de Cruces

Bilbao, Vizcaya, Spain

Hospital del Mar

Barcelona, , Spain

Hospital Universitario de La Princesa

Madrid, , Spain

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, , Ukraine

Royal Devon and Exeter Hospital NHS Trust

Exeter, Devon, United Kingdom

Cognition Health Unit 2

Plymouth, Devon, United Kingdom

Salford Royal NHS Foundation Trust

Salford, Greater Manchester, 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

Countries

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

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-003941-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

0170

Identifier Type: -

Identifier Source: org_study_id