This study will look at whether an investigational drug called TD-9855 works and how safe it is for treating symptomatic neurogenic orthostatic hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA) or pure autonomic failure (PAF)

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2018-003289-15-ES
• Date of registration: 27/06/2019
• Prospective Registration: No
• Primary sponsor: Theravance Biopharma Ireland Limited
• Public title: This study will look at whether an investigational drug called TD-9855 works and how safe it is for treating symptomatic neurogenic orthostatic hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA) or pure autonomic failure (PAF)
• Scientific 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 - Phase 3 Clinical Effect of TD-9855 for Treating snOH in Subjects With Primary Autonomic Failure
• Date of first enrolment: 26/06/2019
• Target sample size: 188
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003289-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Canada, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, Russian Federation, Spain, Ukraine, United Kingdom, United States

Contacts

• Name: Dr. Brett Haumann
• Affiliation: Theravance Biopharma Ireland Limited

• Name: Dr. Brett Haumann
• Affiliation: Theravance Biopharma Ireland Limited

Key inclusion & exclusion criteria

Inclusion criteria:
*Subject is male or female and at least 30 years old.
*Subject is female and must be nonpregnant and nonlactating. A woman of childbearing potential must have a documented negative pregnancy test at screening.
*If sexually active, the subject must agree to use a highly effective method of birth control with partners of childbearing potential during the study and for 1 month after the last study medication dose. Male subjects should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with TD-9855 and for 1 month after the last dose to avoid exposing an embryo
or fetus to TD-9855.
*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 =60 degrees 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.
*Subject is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
*Subject 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 95
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 95

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 is unable or unwilling to complete all protocol specified procedures including questionnaires.
*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 any malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma within the past 2 years prior to screening.
*Subject 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).
*Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of the subject to give informed consent or interfere with the conduct of the study.
*Subject is currently receiving any investigational drug or has received an investigational drug within 30 days of dosing. An investigational drug is defined as nonregulatory agency approved drug (e.g., Food and Drug Administration).
*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 t

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

Intervention(s)

Product Code: TD-9855
Pharmaceutical Form: Tablet
INN or Proposed INN: ampreloxetine
CAS Number: 1227056-84-9
Current Sponsor code: TD-9855
Other descriptive name: TD-9855
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 4.

Main Objective: To evaluate the efficacy of TD-9855 in subjects with multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) experiencing symptomatic neurogenic orthostatic hypotension (snOH) compared with placebo at Week 4, as measured by the change from baseline of the Orthostatic Hypotension Symptom Assessment (OHSA) Question 1 (OHSA#1) score.

Secondary Objective: - To evaluate the efficacy of TD-9855 by symptom and activity assessments using OHSA and the Orthostatic Hypotension Daily Activities Scale (OHDAS).
- To evaluate the efficacy of TD-9855 using the Patient Global Impression of Change (PGI-C), disease-specific instruments, Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire-8 (PDQ-8),
Unified Multiple System Atrophy Rating Scale (UMSARS), Composite Autonomic Symptoms Score-31 (COMPASS-31), and incidence of falls.
- To evaluate the efficacy of TD-9855 using standing blood pressure during orthostatic standing test.
- To evaluate the safety and tolerability of TD-9855, including adverse events (AEs) and changes in blood pressure (BP), heart rate (HR), electrocardiogram (ECG), Columbia Suicide Severity Rating Scale (C-SSRS), and laboratory tests.

Primary end point(s): Change from baseline in OHSA#1 (dizziness, lightheadedness, feeling faint, or feeling like blacking out) at Week 4.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 4.

Secondary end point(s): • Change from baseline in OHSA composite score in Weeks 1 to 4
• Change from baseline in OHDAS composite score in Weeks 1 to 4
• PGI-C at Week 4
• Incidence of falls
• Standing systolic blood pressure during orthostatic standing test

Additional key secondary endpoints by disease type include:
For subjects with PD
• Change from baseline in UPDRS at Week 4
• Change from baseline in PDQ-8 at Week 4
For subjects with MSA
• Change from baseline in COMPASS-31 at Week 4
• Change from baseline in UMSARS at Week 4

Secondary ID(s)

0169

2018-003289-15-GB

Source(s) of Monetary Support

Theravance Biopharma Ireland Limited

Ethics review

Status: Approved
Approval date:
Contact: