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Clinical Effect Durability of TD-9855 for Treating snOH in Subjects With Primary Autonomic Failure

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ClinicalTrials.gov Identifier: NCT03829657
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Theravance Biopharma

Tracking Information
First Submitted Date  ICMJE January 10, 2019
First Posted Date  ICMJE February 4, 2019
Last Update Posted Date March 13, 2019
Actual Study Start Date  ICMJE February 22, 2019
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 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. PGI-S uses a 7 point scale ranging from 1 (Normal, not at all ill) to 7 (Extremely ill).
Original Primary Outcome Measures  ICMJE
 (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.
Change History Complete list of historical versions of study NCT03829657 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Effect Durability of TD-9855 for Treating snOH in Subjects With Primary Autonomic Failure
Official Title  ICMJE 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 TD-9855 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 TD-9855 in subjects with primary autonomic failures (MSA, PD, or PAF) and snOH. The study consists of 3 periods: (i) 16-week open-label (OL) treatment with TD-9855, (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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Open Label Extension followed by Randomized Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Symptomatic Neurogenic Orthostatic Hypotension
Intervention  ICMJE
  • Drug: TD-9855
    Oral tablet, QD (Daily)
  • Drug: Placebo
    Oral tablet, QD
Study Arms  ICMJE
  • Experimental: TD-9855 (Open Label (OL))
    Participants will receive TD-9855 as a single, oral, daily dose of active drug for 16 weeks.
    Intervention: Drug: TD-9855
  • Experimental: TD-9855
    After completing the OL, participants randomized to TD-9855 will receive single, oral, daily dose of active drug for a further 6 weeks.
    Intervention: Drug: TD-9855
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 31, 2019)
258
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 TD-9855. No minimum score of OHSA#1 is required to enter V1 of Study 0170.
  • 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 snOH, as demonstrated by a ≥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 impaired autonomic reflexes, as determined by absence of Phase IV BP overshoot after release of the Valsalva strain.
  • 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, diabetes mellitus, diabetes insipidus, diabetic neuropathy, amyloidosis, or 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 (e.g., ephedrine, dihydroergotamine, or fludrocortisone), within 7 days prior to V1. These medications must be tapered off post-randomization. Tapering will follow the product's approved package insert (if applicable). Midodrine and droxidopa 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Theravance Biopharma Call Center 1-855-633-8479 medinfo@theravance.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03829657
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Theravance Biopharma
Study Sponsor  ICMJE Theravance Biopharma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Monitor Theravance Biopharma
PRS Account Theravance Biopharma
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP