Clinical trial NCT05696717: Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic NOH in Participants with Multiple System Atrophy
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Symptomatic Neurogenic Orthostatic Hypotension
MSA - Multiple System Atrophy
Lead sponsor: Theravance Biopharma
Sponsor class: INDUSTRY
First posted: 2023-01-25
Enrollment: 102
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 followed by Randomized Parallel Assignment
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Change in OHSA composite score at Week 8 during the double-blind RW period
timeFrame: 8-week randomized withdrawal period (Week 12 to Week 20)
Secondary outcomes:
measure: Change from baseline in OHDAS item 1 (activities that require standing for a short time) at Week 8 post randomization
timeFrame: 8-week randomized withdrawal period (Week 12 to Week 20)
measure: Change from baseline in OHDAS item 3 (activities that require walking for a short time) at Week 8 post randomization
timeFrame: 8-week randomized withdrawal period (Week 12 to Week 20)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Movement Disorders Center of Arizona
state: Arizona
city: Fountain Valley
country: United States
facility: The Parkinson's and Movement Disorder Institute
state: California
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: Washington DC
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Boca Raton
country: United States
facility: Parkinson's Disease And Movement Disorders Center of Boca Raton
state: Florida
city: Boca Raton
country: United States
facility: SFM Clinical Research, LLC
state: Florida
city: Naples
country: United States
facility: Aqualane Clinical Research
state: Florida
city: Port Charlotte
country: United States
facility: Neurostudies, Inc
state: Florida
city: Tampa
country: United States
facility: University of South Florida Ataxia Research Center
state: Florida
city: Atlanta
country: United States
facility: Theravance Biopharma Investigative Site
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Pacific Neuroscience
state: Hawaii
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: Boston
country: United States
facility: TBPH Investigative Site
state: Massachusetts
city: Worcester
country: United States
facility: Massachusetts Chan Medical School
state: Massachusetts
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: New York
country: United States
facility: NYU Langone Health NYU Dysautonomia Center
state: New York
city: New York
country: United States
facility: The Neurological Institute at Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
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: Houston
country: United States
facility: Theravance Biopharma Investigative Site
state: Texas
city: Caba
country: Argentina
facility: INEBA Instituto Neurociencias Buenos Aires
city: Caba
country: Argentina
facility: Hospital General de Agudos Jose Maria Ramos Mejía
city: Caba
country: Argentina
facility: Hospital Británico de Buenos Aires
city: Caba
country: Argentina
facility: Instituto Fleni
city: Caba
country: Argentina
facility: Médico/Hospital de la Policía Federal Churruca Visca
city: Mendoza
country: Argentina
facility: Fundación Scherbovsky
city: Clayton
country: Australia
facility: Theravance Biopharma Investigative Site
state: Victoria
city: Melbourne
country: Australia
facility: Theravance Biopharma Investigative Site
state: Victoria
city: Parkville
country: Australia
facility: Theravance Biopharma Investigative Site
state: Victoria
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Tulln
country: Austria
facility: Universitatsklinikum Tulln
city: Edegem
country: Belgium
facility: UZA - Antwerp University Hospital - Department of Neurology
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba S\C LTDA
state: PR
city: Belo Horizonte
country: Brazil
facility: Hospital de Clínicas - Universidade Federal de Minas Gerais (HC - UFMG)
city: Porto Alegre
country: Brazil
facility: Centro de Pesquisa Clínica (CPC) do Hospital das Clínicas de Porto Alegre (HCPA)
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas - PUCRS
city: Salvador
country: Brazil
facility: Hospital da Bahia
city: Calgary
country: Canada
facility: University of Calgary - Health Sciences Centre
state: Alberta
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Tallinn
country: Estonia
facility: Astra Clinic (Clinic4U)
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Nimes
country: France
facility: Theravance Biopharma Investigative Site
state: Occitanie
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux Health
city: Toulouse
country: France
facility: Centre d'Investigation Clinique Hôpital Pierre Paul Rique
city: Gera
country: Germany
facility: Praxis Dr. Oehlwein, Outpatient Clinic
state: Thueringen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin- Campus Mitte
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Tel Aviv
country: Israel
facility: Theravance Biopharma Investigative Site
city: Bologna
country: Italy
facility: IRCCS Istituto de Scienze Neurologiche di Bologna (ISNB)
city: Milano
country: Italy
facility: Parkinson's Centre of Ospedale CTO
city: Rome
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Salerno
country: Italy
facility: AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno
city: Terni
country: Italy
facility: Azienda Ospedaliera Santa Maria di Terni
city: Trento
country: Italy
facility: Santa Chiara Hospital
city: Tricase
country: Italy
facility: Pia Fond. Cardinale Giovanni Panico Azienda Ospedaliera
city: Grafton
country: New Zealand
facility: Theravance Biopharma Investigative Site
state: Auckland
city: Christchurch
country: New Zealand
facility: Theravance Biopharma Investigative Site
city: Gdańsk
country: Poland
facility: Neurocentrum-Miwomed
city: Katowice
country: Poland
facility: Neuro-Care Sp. z o.o. Sp. Komandytowa
city: Kraków
country: Poland
facility: Krakowska Akademia Neurologii Sp.zo.o.
city: Oświęcim
country: Poland
facility: Instytut Zdrowia dr Boczarska-Jedynak Sp. z o.o., Sp.k.
city: Torres Vedras
country: Portugal
facility: CNS-Campus Neurologico Senior
city: Terrassa
country: Spain
facility: Fundació Assistencial Mutua de Terrassa
state: Barcelona
city: Barakaldo
country: Spain
facility: Hospital Germans Trias i Pujol, Department of Neurology
state: Bizkaia
city: Barakaldo
country: Spain
facility: Instituto Investigación Sanitaria Biocruces
state: Bizkaia
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Infante Sofia Paseo Europa
city: Taipei City
country: Taiwan
facility: Theravance Biopharma Investigative Site
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: London
country: United Kingdom
facility: Barts Health
city: London
country: United Kingdom
facility: Autonomic Unit, National Hospital for Neurology & Neurosurgery
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
Study officials:
References: