Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (REDWOOD)

• ClinicalTrials.gov Identifier: NCT03829657
• Recruitment Status: Terminated
• First Posted: February 4, 2019
• Results First Posted: January 20, 2023
• Last Update Posted: January 20, 2023
• Sponsor: Theravance Biopharma
• Information provided by (Responsible Party): Theravance Biopharma

Tracking Information

• First Submitted Date: January 10, 2019
• First Posted Date: February 4, 2019
• Results First Submitted Date: November 8, 2022
• Results First Posted Date: January 20, 2023
• Last Update Posted Date: January 20, 2023
• Actual Study Start Date: February 22, 2019
• Actual Primary Completion Date: November 10, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 29, 2022)

Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]

Treatment failure was defined as proportion of participants who met the following criteria at Week 6 following randomization: Change (worsening) from baseline in Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA#1) score of 1.0 point and worsening of disease severity as assessed by a 1-point change in Patient Global Impression of Severity (PGI-S). OHSA Question #1 assessed dizziness, lightheadedness, feeling faint, or feeling like you might blackout. PGI-S assessed patient's impression of disease severity. Least squares mean here is the model-based proportion of participants with treatment failure using logistic regression.

Original Primary Outcome Measures (submitted: January 31, 2019)

• Change (worsening) from baseline in OHSA#1 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  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.
• Worsening of disease severity as assessed by a change in PGI-S at Week 22. [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  Score change from baseline on Patient Global Impression of Severity (PGI-S). PGI-S assesses patient's impression of disease severity.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: January 31, 2019)

• Change from baseline in OHSA#1 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  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.
• Change from baseline in OHSA composite score at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  Orthostatic Hypotension Symptom Assessment (OHSA) is an assessment of the severity of symptoms from low blood pressure.
• Change from baseline in OHDAS composite score at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  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.
• Standing Systolic blood pressure (SBP) during orthostatic standing test at Week 22 [ Time Frame: Week 22 ]
  SBP taken during the standing portion of the orthostatic standing test.
• Change from baseline in percent of time spent in supine, sitting, and standing position as measured by a wearable device at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
• Change from baseline in UPDRS at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  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 22
• Change from baseline in PDQ-8 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  Parkinson's Disease Questionnaire-8 (PDQ-8) is an assessment for Parkinson's Disease (PD) subjects. Outcome measure only applies to subjects with PD.
• Change from baseline in UMSARS at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  Unified Multiple System Atrophy Rating Scale (UMSARS) is an assessment for Multiple System Atrophy (MSA) subjects. Outcome measure only applies to subjects with MSA.
• Change from baseline in COMPASS-31 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  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).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
• Official Title: A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure
• Brief Summary: A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure
• Detailed Description: Phase 3, multi-center, randomized withdrawal study to evaluate the sustained benefit in efficacy and safety of ampreloxetine in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH. The study consists of 3 periods: (i) 16-week open-label (OL) treatment with ampreloxetine, (ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up (only for patients who do not enroll in Study 0171 (long-term extension safety study)).
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Open Label Extension followed by Randomized Parallel Assignment

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

Condition

• Symptomatic Neurogenic Orthostatic Hypotension
• MSA
• Parkinson's Disease (PD)
• Pure Autonomic Failure (PAF)

Intervention

• Drug: ampreloxetine
  Oral tablet, QD (Daily)
  Other Name: TD-9855
• Drug: Placebo
  Oral tablet, QD

Study Arms

• Experimental: ampreloxetine (Open Label (OL))
  Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.
  Intervention: Drug: ampreloxetine
• Experimental: ampreloxetine
  After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.
  Intervention: Drug: ampreloxetine
• Placebo Comparator: Placebo
  After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 15, 2021): 203
• Original Estimated Enrollment (submitted: January 31, 2019): 258
• Actual Study Completion Date: November 10, 2021
• Actual Primary Completion Date: November 10, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria (For 0169 Completers Group):

• Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with ampreloxetine. Only subjects with OHSA#1 score of ≤7 will be eligible for randomization for the double-blind treatment period.
• Subject has a minimum of 80% study medication compliance in Study 0169.

Inclusion Criteria (For De Novo Group):

• Subject is male or female and at least 30 years old.
• Subject must meet the diagnostic criteria of symptomatic nOH, as demonstrated by a sustained reduction in BP of ≥20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 min of being tilted-up ≥60o from a supine position as determined by a tilt-table test.
• Subject must score at least a 4 on the OHSA#1 at V1.
• 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 documented impaired autonomic reflexes, including the Valsalva maneuver performed within 24 months from the date of randomization
• Subject has plasma Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated position for 30 minutes.

Exclusion Criteria (For 0169 Completers Group):

• Subject has a medical, laboratory, or surgical issue(s) deemed by the investigator to be clinically significant.
• Subject has an uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
• Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.

Exclusion Criteria (For De Novo Group):

• Subject has a known systemic illness known to produce autonomic neuropathy, including but not limited to amyloidosis, and autoimmune neuropathies.
• Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (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 V1 or requires concomitant use until the follow-up visit.

• Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to V1.

  • Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1.
• Subject 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).
• Subject has a clinically unstable coronary artery disease, or has had a major cardiovascular or neurological event in the past 6 months.
• Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
• 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 a clinically significant abnormal laboratory finding (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/1.73 m2, 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 Columbia Suicide Severity Rating Scale (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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Bulgaria, Canada, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Russian Federation, Spain, Ukraine, United Kingdom, United States
• Removed Location Countries: Argentina

Administrative Information

• NCT Number: NCT03829657
• Other Study ID Numbers: 0170; 2018-003941-41 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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.

• Current Responsible Party: Theravance Biopharma
• Original Responsible Party: Same as current
• Current Study Sponsor: Theravance Biopharma
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Monitor; Theravance Biopharma

• PRS Account: Theravance Biopharma
• Verification Date: December 2022