Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic NOH in Participants with Multiple System Atrophy

Phase 3

Recruiting

• Conditions: MSA - Multiple System Atrophy; Symptomatic Neurogenic Orthostatic Hypotension
• Interventions: Drug: Ampreloxetine; Drug: Placebo

• Registration Number: NCT05696717
• Lead Sponsor: Theravance Biopharma

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-01-13
• Study First Submitted QC: 2023-01-13
• Study First Posted: 2023-01-25
• Study Start: 2023-06-27
• Status Verified: 2024-11
• Primary Completion: 2024-12
• Last Update Submitted: 2024-12-20
• Last Update Posted: 2024-12-27
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 102

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Long-Term Extension Period	Ampreloxetine	Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.
Ampreloxetine (Randomized Withdrawal)	Placebo	After completing the open label, participants are randomized to either ampreloxetine or placebo receiving a single, oral, daily dose of active drug or placebo for a further 8 weeks.
Ampreloxetine (Open Label)	Ampreloxetine	Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.
Ampreloxetine (Randomized Withdrawal)	Ampreloxetine	After completing the open label, participants are randomized to either ampreloxetine or placebo receiving a single, oral, daily dose of active drug or placebo for a further 8 weeks.

Primary Outcome Measures

Name	Time	Method
Change in OHSA composite score at Week 8 during the double-blind RW period	8-week randomized withdrawal period (Week 12 to Week 20)	Score change from baseline on the composite of Questions 1 - 6 of the Orthostatic Hypotension Symptom Assessment (OHSA).

Secondary Outcome Measures

Name	Time	Method
Change from baseline in OHDAS item 1 (activities that require standing for a short time) at Week 8 post randomization	8-week randomized withdrawal period (Week 12 to Week 20)	Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.
Change from baseline in OHDAS item 3 (activities that require walking for a short time) at Week 8 post randomization	8-week randomized withdrawal period (Week 12 to Week 20)	Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.

Trial Locations

Locations (69)

Hospital Británico de Buenos Aires; 🇦🇷 Caba, Argentina

Neurostudies, Inc; 🇺🇸 Port Charlotte, Florida, United States

Movement Disorders Center of Arizona; 🇺🇸 Scottsdale, Arizona, United States

The Parkinson's and Movement Disorder Institute; 🇺🇸 Fountain Valley, California, United States

UC San Diego Movement Disorder Center; 🇺🇸 La Jolla, California, United States

Instituto Fleni; 🇦🇷 Caba, Argentina

Stanford Neuroscience Health Center; 🇺🇸 Palo Alto, California, United States

Medstar Georgetown University Hospital; 🇺🇸 Washington DC, District of Columbia, United States

Parkinson's Disease And Movement Disorders Center of Boca Raton; 🇺🇸 Boca Raton, Florida, United States

SFM Clinical Research, LLC; 🇺🇸 Boca Raton, Florida, United States

Aqualane Clinical Research; 🇺🇸 Naples, Florida, United States

University of South Florida Ataxia Research Center; 🇺🇸 Tampa, Florida, United States

Theravance Biopharma Investigative Site; 🇨🇳 Taipei City, Taiwan

Hawaii Pacific Neuroscience; 🇺🇸 Honolulu, Hawaii, 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

TBPH Investigative Site; 🇺🇸 Boston, Massachusetts, United States

Massachusetts Chan Medical School; 🇺🇸 Worcester, Massachusetts, United States

Quest Research Institute; 🇺🇸 Farmington Hills, Michigan, United States

NYU Langone Health NYU Dysautonomia Center; 🇺🇸 New York, New York, United States

The Neurological Institute at Columbia University Medical Center; 🇺🇸 New York, New York, United States

University of Cincinnati Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

INEBA Instituto Neurociencias Buenos Aires; 🇦🇷 Caba, Argentina

Hospital General de Agudos Jose Maria Ramos Mejía; 🇦🇷 Caba, Argentina

Médico/Hospital de la Policía Federal Churruca Visca; 🇦🇷 Caba, Argentina

Fundación Scherbovsky; 🇦🇷 Mendoza, Argentina

Medical University of Innsbruck; 🇦🇹 Innsbruck, Austria

Universitatsklinikum Tulln; 🇦🇹 Tulln, Austria

UZA - Antwerp University Hospital - Department of Neurology; 🇧🇪 Edegem, Belgium

Instituto de Neurologia de Curitiba S\C LTDA; 🇧🇷 Curitiba, PR, Brazil

Hospital de Clínicas - Universidade Federal de Minas Gerais (HC - UFMG); 🇧🇷 Belo Horizonte, Brazil

Centro de Pesquisa Clínica (CPC) do Hospital das Clínicas de Porto Alegre (HCPA); 🇧🇷 Porto Alegre, Brazil

Hospital São Lucas - PUCRS; 🇧🇷 Porto Alegre, Brazil

Hospital da Bahia; 🇧🇷 Salvador, Brazil

University of Calgary - Health Sciences Centre; 🇨🇦 Calgary, Alberta, Canada

Bispebjerg Hospital; 🇩🇰 Copenhagen, Denmark

Astra Clinic (Clinic4U); 🇪🇪 Tallinn, Estonia

Tartu University Hospital; 🇪🇪 Tartu, Estonia

Centre Hospitalier Universitaire de Bordeaux Health; 🇫🇷 Bordeaux, France

Centre d'Investigation Clinique Hôpital Pierre Paul Rique; 🇫🇷 Toulouse, France

Praxis Dr. Oehlwein, Outpatient Clinic; 🇩🇪 Gera, Thueringen, Germany

Charité - Universitätsmedizin Berlin- Campus Mitte; 🇩🇪 Berlin, Germany

Charite Universitaetsmedizin Berlin; 🇩🇪 Berlin, Germany

Semmelweis Egyetem; 🇭🇺 Budapest, Hungary

IRCCS Istituto de Scienze Neurologiche di Bologna (ISNB); 🇮🇹 Bologna, Italy

Parkinson's Centre of Ospedale CTO; 🇮🇹 Milano, Italy

Azienda Ospedaliera Universitaria Policlinico Tor Vergata; 🇮🇹 Rome, Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS; 🇮🇹 Rome, Italy

AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno; 🇮🇹 Salerno, Italy

Azienda Ospedaliera Santa Maria di Terni; 🇮🇹 Terni, Italy

Santa Chiara Hospital; 🇮🇹 Trento, Italy

Pia Fond. Cardinale Giovanni Panico Azienda Ospedaliera; 🇮🇹 Tricase, Italy

Neurocentrum-Miwomed; 🇵🇱 Gdańsk, Poland

Neuro-Care Sp. z o.o. Sp. Komandytowa; 🇵🇱 Katowice, Poland

Krakowska Akademia Neurologii Sp.zo.o.; 🇵🇱 Kraków, Poland

Instytut Zdrowia dr Boczarska-Jedynak Sp. z o.o., Sp.k.; 🇵🇱 Oświęcim, Poland

CNS-Campus Neurologico Senior; 🇵🇹 Torres Vedras, Portugal

Fundació Assistencial Mutua de Terrassa; 🇪🇸 Terrassa, Barcelona, Spain

Hospital Germans Trias i Pujol, Department of Neurology; 🇪🇸 Barakaldo, Bizkaia, Spain

Instituto Investigación Sanitaria Biocruces; 🇪🇸 Barakaldo, Bizkaia, Spain

Hospital Universitario de La Princesa; 🇪🇸 Madrid, Spain

Hospital Universitario Infante Sofia Paseo Europa; 🇪🇸 Madrid, Spain

University Hospitals Birmingham NHS Foundation Trust; 🇬🇧 Birmingham, United Kingdom

Barts Health; 🇬🇧 London, United Kingdom

Autonomic Unit, National Hospital for Neurology & Neurosurgery; 🇬🇧 London, United Kingdom

Salford Royal Hospital; 🇬🇧 Salford, United Kingdom