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

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ClinicalTrials.gov Identifier: NCT05696717
Recruitment Status : Recruiting
First Posted : January 25, 2023
Last Update Posted : April 30, 2024
Sponsor:
Information provided by (Responsible Party):
Theravance Biopharma

Study Description
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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).

Condition or disease Intervention/treatment Phase
Symptomatic Neurogenic Orthostatic Hypotension MSA - Multiple System Atrophy Drug: Ampreloxetine Drug: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open Label followed by Randomized Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : June 27, 2023
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : January 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Ampreloxetine (Open Label)
Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.
 Drug: Ampreloxetine
Oral tablet, QD
Other Name: TD-9855
Placebo Comparator: Ampreloxetine (Randomized Withdrawal)
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.
 Drug: Ampreloxetine
Oral tablet, QD
Other Name: TD-9855

Drug: Placebo
Oral tablet, QD
Active Comparator: Long-Term Extension Period
Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.
 Drug: Ampreloxetine
Oral tablet, QD
Other Name: TD-9855


Outcome Measures
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Primary Outcome Measures :
  1. Change in OHSA composite score at Week 8 during the double-blind RW period [ Time Frame: 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 :
  1. Change from baseline in OHDAS item 1 (activities that require standing for a short time) at Week 8 post randomization [ Time Frame: 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.

  2. Change from baseline in OHDAS item 3 (activities that require walking for a short time) at Week 8 post randomization [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05696717


Contacts
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Contact: Theravance Biopharma 1-855-633-8479 medinfo@theravance.com

Locations
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Sponsors and Collaborators
Theravance Biopharma
More Information
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Responsible Party: Theravance Biopharma
ClinicalTrials.gov Identifier: NCT05696717    
Other Study ID Numbers: 2022-003903-14
First Posted: January 25, 2023    Key Record Dates
Last Update Posted: April 30, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Multiple System Atrophy
Shy-Drager Syndrome
Hypotension, Orthostatic
Hypotension
Atrophy
Pathological Conditions, Anatomical
Vascular Diseases
Cardiovascular Diseases
Primary Dysautonomias
 Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Orthostatic Intolerance