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

MSA - Multiple System Atrophy Clinical Trial

— CYPRESS  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05696717
• Other study ID #: 2022-003903-14
• Status: Recruiting
• Phase: Phase 3
• Start date: June 27, 2023
• Est. completion date: January 2027

Study information

• Verified date: June 2024
• Source: Theravance Biopharma
• Contact: Theravance Biopharma
• Phone: 1-855-633-8479
• Email: medinfo[@]theravance.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 102
• Est. completion date: January 2027
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrophy
• Hypotension
• Hypotension, Orthostatic
• MSA - Multiple System Atrophy
• Multiple System Atrophy
• Shy-Drager Syndrome
• Symptomatic Neurogenic Orthostatic Hypotension

Intervention

Drug:
• Ampreloxetine
Oral tablet, QD
• Placebo
Oral tablet, QD

Locations

Country	Name	City	State
Argentina	Hospital Británico de Buenos Aires	Caba
Argentina	Hospital General de Agudos Jose Maria Ramos Mejía	Caba
Argentina	INEBA Instituto Neurociencias Buenos Aires	Caba
Argentina	Instituto Fleni	Caba
Argentina	Médico/Hospital de la Policía Federal Churruca Visca	Caba
Argentina	Fundación Scherbovsky	Mendoza
Austria	Medical University of Innsbruck	Innsbruck
Austria	Universitatsklinikum Tulln	Tulln
Belgium	UZA - Antwerp University Hospital - Department of Neurology	Edegem
Brazil	Hospital de Clínicas - Universidade Federal de Minas Gerais (HC - UFMG)	Belo Horizonte
Brazil	Instituto de Neurologia de Curitiba S\C LTDA	Curitiba	PR
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
Canada	University of Calgary - Health Sciences Centre	Calgary	Alberta
Chile	Corporación de Investigación de Neurología de Santiago (Usa instalaciones de Clínica Dávila)	Recoleta	Región Metropolinata
Chile	Centro de Estudios de Trastornos del Movimiento Humano (CETRAM)	Santiago	Región Metropolinata
Denmark	Bispebjerg Hospital	Copenhagen
Estonia	Astra Cinic (Clinic4U)	Tallinn
Estonia	Tartu University Hospital	Tartu
France	Centre Hospitalier Universitaire de Bordeaux Health	Bordeaux
Germany	Charite Universitaetsmedizin Berlin	Berlin
Germany	Praxis Dr. Oehlwein, Outpatient Clinic	Gera	Thueringen
Hungary	Semmelweis Egyetem	Budapest
Hungary	Department of Neurology, University of Pécs, Hungary	Pécs
Italy	IRCCS Istituto de Scienze Neurologiche di Bologna (ISNB)	Bologna
Italy	AOU Policlinico-San Marco, Clinica Neurologica	Catania
Italy	Fondazione Università Gabriele D'Annunzio Chieti-Pescara	Chieti
Italy	Fondazione IRCCS CA' Granda Ospedale	Milan
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
Poland	Neurocentrum-Miwomed	Gdansk
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.	Oswiecim
Portugal	CNS-Campus Neurologico Senior	Torres Vedras
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	Fundació Assistencial Mutua de Terrassa	Terrassa	Barcelona
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Autonomic Unit, National Hospital for Neurology & Neurosurgery	London
United Kingdom	Barts Health	London
United Kingdom	Salford Royal Hospital	Salford
United States	Hightower Clinical Research	Ardmore	Oklahoma
United States	Rare Disease Research NC, LLC	Atlanta	Georgia
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	Rush University Medical Center	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Quest Research Institute	Farmington Hills	Michigan
United States	The Parkinson's and Movement Disorder Institute	Fountain Valley	California
United States	Northshore University Health System	Glenview	Illinois
United States	Rare Disease Research NC, LLC	Hillsborough	North Carolina
United States	Hawaii Pacific Neuroscience	Honolulu	Hawaii
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	Science 37	Los Angeles	California
United States	Morgan Family Medical	Meridian	Idaho
United States	Aqualane Clinical Research	Naples	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
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	Stanford Neuroscience Health Center	Palo Alto	California
United States	International Medical Clinic PLLC	Pontiac	Michigan
United States	Neurostudies, Inc.	Port Charlotte	Florida
United States	Movement Disorders Center of Arizona	Scottsdale	Arizona
United States	University of South Florida Ataxia Research Center	Tampa	Florida
United States	Vero Beach Neurology and Research Institute	Vero Beach	Florida
United States	Medstar Georgetown University Hospital	Washington	District of Columbia
United States	Massachusetts Chan Medical School	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Theravance Biopharma

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Brazil,  Canada,  Chile,  Denmark,  Estonia,  France,  Germany,  Hungary,  Italy,  Poland,  Portugal,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in OHSA composite score at Week 8 during the double-blind RW period	Score change from baseline on the composite of Questions 1 - 6 of the Orthostatic Hypotension Symptom Assessment (OHSA).	8-week randomized withdrawal period (Week 12 to Week 20)
Secondary	Change from baseline in OHDAS item 1 (activities that require standing for a short time) at Week 8 post randomization	Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.	8-week randomized withdrawal period (Week 12 to Week 20)
Secondary	Change from baseline in OHDAS item 3 (activities that require walking for a short time) at Week 8 post randomization	Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.	8-week randomized withdrawal period (Week 12 to Week 20)