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Clinical Effect of Ampreloxetine (TD-9855) for Treating snOH in Subjects With Primary Autonomic Failure

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ClinicalTrials.gov Identifier: NCT03750552
Recruitment Status : Recruiting
First Posted : November 22, 2018
Last Update Posted : June 20, 2019
Sponsor:
Information provided by (Responsible Party):
Theravance Biopharma

Brief Summary:
A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and snOH with up to 4 weeks of treatment.

Condition or disease Intervention/treatment Phase
Symptomatic Neurogenic Orthostatic Hypotension Drug: ampreloxetine Drug: Placebo Phase 3

Detailed Description:
A Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and snOH. The study consists of 3 periods: (i) 2-week screening, (ii) 4-week randomized treatment, and (iii) 2-week follow up.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 188 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : September 1, 2020


Arm Intervention/treatment
Experimental: ampreloxetine
Participants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks.
Drug: ampreloxetine
Oral tablet, QD
Other Name: TD-9855

Placebo Comparator: Placebo
Participants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks.
Drug: Placebo
Oral tablet, QD




Primary Outcome Measures :
  1. Change from baseline in OHSA#1 at Week 4 [ Time Frame: Baseline to Week 4 ]
    Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA ). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout.


Secondary Outcome Measures :
  1. Change from baseline in OHSA composite score in Weeks 1 to 4 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4 ]
    Orthostatic Hypotension Symptom Assessment (OHSA ) is an assessment of the severity of symptoms from low blood pressure.

  2. Change from baseline in OHDAS composite score in Weeks 1 to 4 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4 ]

    Orthostatic Hypotension Daily Activities Scale (OHDAS ) is an assessment of how low blood pressure symptoms affect daily life.

    OHDAS is a 4 item assessment that uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.


  3. PGI-C at Week 4 [ Time Frame: Week 4 ]

    Using the Patient Global Impression of Change (PGI-C) scale, a subject rates their total improvement compared to baseline.

    PGI-C uses a 7 point scale ranging from 1 (very much improved) to 7 (very much worse)


  4. Incidence of falls [ Time Frame: Week 4 ]
    Incidence of patient-reported falls.

  5. Standing systolic blood pressure during orthostatic standing test [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4 ]
    Systolic blood pressure taken during the standing portion of the orthostatic standing test.

  6. Change from baseline in UPDRS at Week 4 [ Time Frame: Baseline to Week 4 ]

    Unified Parkinson's Disease Rating Scale (UPDRS) is a clinical rating scale for Parkinson's Disease (PD). Outcome measure only applies to subjects with PD.

    UPDRS is made up of 6 parts. Only parts 2 & 3 (self evaluation of daily activities & clinician scored motor evaluation) will be measured at Week 4.


  7. Change from baseline in PDQ-8 at Week 4 [ Time Frame: Baseline to Week 4 ]
    Parkinson's Disease Questionnaire-8 (PDQ-8) is an assessment for Parkinson's Disease (PD) subjects. Outcome measure only applies to subjects with PD.

  8. Change from baseline in COMPASS-31 at Week 4 [ Time Frame: Baseline to Week 4 ]
    Composite Autonomic Symptoms Score-31 (COMPASS-31) is an assessment that provides a quantitative measure of autonomic symptoms. Outcome measure only applies to subjects with Multiple System Atrophy (MSA).

  9. Change from baseline in UMSARS at Week 4 [ Time Frame: Baseline to Week 4 ]
    Unified Multiple System Atrophy Rating Scale (UMSARS) is an assessment for Multiple System Atrophy (MSA) subjects. Outcome measure only applies to subjects with MSA.



Information from the National Library of Medicine

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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:

  • Subject is male or female and at least 30 years old.
  • Subject must meet the diagnostic criteria of snOH, as demonstrated by a ≥20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 minutes of being tilted-up to ≥60o from a supine position as determined by a tilt-table test.
  • Subject must score at least a 4 on the Orthostatic Hypotension Symptom Assessment Question #1 at randomization visit.
  • 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 impaired autonomic reflexes, as determined by absence of Phase IV BP overshoot after release of the Valsalva strain.
  • Subject has plasma NE levels >100 pg/mL after being in seated position for 30 minutes.

Exclusion Criteria:

  • Subject has a known systemic illness known to produce autonomic neuropathy, including but not limited to diabetes mellitus, diabetes insipidus, diabetic neuropathy, amyloidosis, and autoimmune neuropathies.
  • Subject has a known intolerance to other NRIs or 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 randomization or requires concomitant use until the follow-up visit.
  • Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension (e.g., ephedrine, dihydroergotamine, or fludrocortisone), within 7 days prior to randomization visit. These medications must be tapered off postrandomization. Tapering will follow the product's United States (US) package insert. Midodrine and droxidopa must be tapered off at least 7 days prior to randomization.
  • Subject has a known or suspected alcohol or substance abuse within the past 12 months (DSM-IV-TR® definition of alcohol or substance abuse).
  • Subject has a clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months.
  • Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to randomization.
  • 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 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 findings (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/1.73m2, 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 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.

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): NCT03750552


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

Locations
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United States, Arizona
St. Joseph's Hospital & Medical Center Recruiting
Phoenix, Arizona, United States, 85013
United States, California
Collaborative Neuroscience Network, LLC Recruiting
Long Beach, California, United States, 90806
United States, Colorado
Colorado Springs Neurological Associates, PC Recruiting
Colorado Springs, Colorado, United States, 80907
United States, Florida
Boca Raton Regional Hospital, Marcus Neuroscience Institute Recruiting
Boca Raton, Florida, United States, 33486
Parkinson's Disease and Movement Disorders Center Recruiting
Boca Raton, Florida, United States, 33486
Neurostudies, Inc Recruiting
Port Charlotte, Florida, United States, 33952
United States, Kansas
University of Kansas Medical Center Recruiting
Kansas City, Kansas, United States, 66160
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
United States, New York
New York University Langone Health Recruiting
New York, New York, United States, 10016
United States, North Carolina
Wake Forest University Baptist Health Sciences Recruiting
Winston-Salem, North Carolina, United States, 27157
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
United States, Washington
Inland Northwest Research Recruiting
Spokane, Washington, United States, 99202
Sponsors and Collaborators
Theravance Biopharma
Investigators
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Study Director: Medical Monitor Theravance Biopharma

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Responsible Party: Theravance Biopharma
ClinicalTrials.gov Identifier: NCT03750552     History of Changes
Other Study ID Numbers: 0169
2018-003289-15 ( EudraCT Number )
First Posted: November 22, 2018    Key Record Dates
Last Update Posted: June 20, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Theravance Biopharma:
Symptomatic Neurogenic Orthostatic Hypotension
snOH
multiple system atrophy
MSA
Parkinson's disease
PD
pure autonomic failure
PAF
primary autonomic failure
SEQUOIA
ampreloxetine
169
low blood pressure
dizziness
fainting
blacking out
lightheadedness
norepinephrine
hypotension
orthostatic hypotension
OH

Additional relevant MeSH terms:
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Hypotension
Hypotension, Orthostatic
Pure Autonomic Failure
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases