- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02705755
TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH)
A Phase 2 Study to Assess the Effect of TD-9855 in Subjects With Neurogenic Orthostatic Hypotension
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Part A followed a daily, single-escalating-dose design, starting with placebo on Day 1, followed by a dose of 2.5 mg TD-9855 on Day 2, and proceeding to higher daily doses of TD-9855 up to a maximum dose of 20 mg based on safety, tolerability, and determination of a pressor effect.
The starting dose in Part A was initially set to 1 mg (Day 2), escalating to a maximum dose of 10 mg (Day 5), but this was revised to start at 2.5 mg (Day 2) and escalate to 20 mg (Day 5) in protocol amendment 2 (Section 9.8.1).
Part B followed a randomized, placebo-controlled, parallel design, evaluating an acute dose of TD-9855 that was determined to have a pressor effect and to be generally well tolerated for a given subject from Part A.
Subjects who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 by tablet daily for up to 5 months (20 weeks) during Part C.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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California
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Long Beach, California, United States, 90806
- Theravance Biopharma Investigational Site
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Michigan
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Farmington Hills, Michigan, United States, 48334
- Theravance Biopharma Investigational Site
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New Jersey
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Berlin, New Jersey, United States, 08009
- Theravance Biopharma Investigational Site
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New York
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New York, New York, United States, 10016
- Theravance Biopharma Investigational Site
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Tennessee
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Nashville, Tennessee, United States, 37232
- Theravance Biopharma Investigational Site
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Texas
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Dallas, Texas, United States, 75390
- Theravance Biopharma Investigational Site
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Diagnosed with symptomatic orthostatic hypotension due to Parkinson's disease, multiple system atrophy, or pure autonomic failure, (i.e. neurogenic orthostatic hypotension).
- At screening, subject must meet the diagnostic criteria of neurogenic orthostatic hypotension, as demonstrated by a ≥ 30 mm Hg drop in systolic blood pressure (SBP) within 5 minutes of standing.
- Impaired autonomic reflexes, as determined by absence of BP overshoot during phase IV of the Valsalva maneuver, in subjects where Valsalva is performed, as appropriate.
- For the optional open-label extension study subjects must have demonstrated a pressor effect and completed dosing in Part A.
Exclusion Criteria:
- Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies.
- Concomitant use of vasoconstricting agents for the purpose of increasing BP such as ephedrine, dihydroergotamine, or midodrine must be stopped at least 2 days or five half lives (whichever is longer) prior to dosing on Day 1 of Part A and C, and throughout the duration of Part C. Subjects previously enrolled in Part A under previous versions of the protocol will continue taking fludrocortisone during the washout period and in Part C at the dose and regimen used in Part A. For new subjects enrolling in Part A under Amendment 3, fludrocortisone use in both Parts of the study and during the washout period will be limited to 0.1 mg QD.
- Concomitant use of anti-hypertensive medication for the treatment of essential hypertension unrelated to autonomic dysfunction.
- Known or suspected alcohol or substance abuse within the past 12 months.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: TD-9855 Part A
Subjects will receive placebo and escalating single doses of TD-9855
|
Administered orally.
Administered orally.
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Experimental: TD-9855 Part B
Subjects will receive a single dose of TD-9855 or placebo.
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Administered orally.
Administered orally.
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Experimental: TD-9855 Part C
Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.
|
Administered orally.
Administered orally.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP)
Time Frame: 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
|
Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1).
|
7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
|
Part B: Change From Baseline in Seated SBP
Time Frame: Baseline and 7 hours post-dose on Day 1
|
Baseline was defined as the pre-dose measurement on Day 1 of Part B.
|
Baseline and 7 hours post-dose on Day 1
|
Part C: Change From Baseline in Likert Scale Score at Week 4
Time Frame: Baseline to Week 4
|
The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA).
The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.
A higher score indicates a worse outcome.
Baseline was defined as the pre-lunch measurement on Day -1.
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Baseline to Week 4
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours
Time Frame: Baseline to a single time point between 6 to 8 hours post-dose
|
The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA).
The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.
A higher score indicates a worse outcome.
Baseline was defined as the pre-dose measurement on Day 1 for Part A and Part B. Data was collected a one point between 6 and 8 hours post-dose.
|
Baseline to a single time point between 6 to 8 hours post-dose
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Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score
Time Frame: Baseline to a single time point between 6 to 8 hours post-dose
|
The OHSA is made up of a 6-item symptoms assessment.
All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.
Activities that were marked as zero or "cannot be done for other reasons" at baseline were not included in the scoring.
The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA.
A reduction in composite score indicates an improvement in symptoms.
Baseline was defined as the pre-dose measurement on Day 1 for Part A and Part B. Data was collected a one point between 6 and 8 hours post-dose.
|
Baseline to a single time point between 6 to 8 hours post-dose
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Part A: Change From Time-matched Placebo in Standing SBP
Time Frame: 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
|
Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1).
SBP was measured after 5 minutes of standing.
|
4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
|
Part B: Change From Baseline in Standing SBP
Time Frame: Baseline, 4 and 7 hours post-dose on Day 1
|
SBP was measured after 3 minutes of standing.
Baseline was defined as the pre-dose measurement on Day 1 of Part B.
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Baseline, 4 and 7 hours post-dose on Day 1
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Part A: Change From Time-matched Placebo in Seated SBP
Time Frame: 4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing)
|
Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1).
|
4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing)
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Part B: Change From Baseline in Seated SBP
Time Frame: Baseline and 4, 7, 9 and 12 hours post-dose on Day 1
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Baseline was defined as the pre-dose measurement on Day 1 of Part B.
|
Baseline and 4, 7, 9 and 12 hours post-dose on Day 1
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Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST)
Time Frame: 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
|
Blood pressure (BP) and heart rate (HR) measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min.
The standing time was measured with a chronometer and the duration of standing was recorded.
The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test.
In either case, the total duration was recorded.
Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1) of Part A.
|
4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
|
Part B: Change From Baseline in Duration of Standing During the OST
Time Frame: Baseline and 7 hours post-dose on Day 1
|
BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min.
The standing time was measured with a chronometer and the duration of standing was recorded.
The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test.
In either case, the total duration was recorded.
Baseline was defined as the predose measurement on Day 1 of Part B.
|
Baseline and 7 hours post-dose on Day 1
|
Part C: Change From Baseline in the Composite OHSA Score
Time Frame: Baseline to Day 169
|
The OHSA is made up of a 6-item symptoms assessment.
All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting "cannot be done for other reasons."
Activities that were marked as zero or "cannot be done for other reasons" at baseline were not included in the scoring.
The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA.
Baseline was defined as the pre-lunch measurement on Day -1.
|
Baseline to Day 169
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Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS)
Time Frame: Baseline to Day 169
|
The OHDAS is made up of a 4-item daily activity assessment.
All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting "cannot be done for other reasons."
Activities that were marked as zero or "cannot be done for other reasons" at baseline were not included in the scoring.
The composite OHDAS score is the average of the response scores (for non-missing data) to the 4 questions of OHDAS.
Baseline was defined as the pre-lunch measurement on Day -1.
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Baseline to Day 169
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Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score
Time Frame: Baseline to Day 169
|
The OHQ is a 2-component questionnaire made up of 6-item symptoms assessment referred to as OHSA, and a 4-item daily activity assessment referred to as the OHDAS. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting "cannot be done for other reasons." Activities that were marked as zero or "cannot be done for other reasons" at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. The composite OHDAS score is the average of the response scores (for non-missing data) to the 4 questions of OHDAS. The OHQ composite score is the average of the OHSA and OHDAS composite scores. Baseline was defined as the pre-lunch measurement on Day -1. |
Baseline to Day 169
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Part C: Change From Baseline in Standing SBP
Time Frame: Baseline to Day 169
|
SBP was measured after 3 minutes of standing.
Baseline was defined as the pre-lunch measurement on Day 1.
|
Baseline to Day 169
|
Part C: Change From Baseline in Seated SBP
Time Frame: Baseline to Day 169
|
Baseline was defined as the pre-breakfast measurement on Day 1.
|
Baseline to Day 169
|
Part C: Change From Baseline in Duration of Standing During the OST
Time Frame: Baseline to Day 169
|
BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min.
The standing time was measured with a chronometer and the duration of standing was recorded.
The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test.
In either case, the total duration was recorded.
Baseline was defined as the pre-breakfast measurement on Day 1.
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Baseline to Day 169
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Part C: Change From Baseline in Supine SBP to Seated SBP
Time Frame: Baseline to Day 169
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Baseline is defined as pre-breakfast measurement on Day 1.
The difference in SBP from a supine to a seated position was measured at baseline and at each time point.
The change from baseline was calculated at each time point.
|
Baseline to Day 169
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Medical Monitor, Theravance Biopharma, US, Inc.
Publications and helpful links
General Publications
- Kaufmann H, Vickery R, Wang W, Kanodia J, Shibao CA, Norcliffe-Kaufmann L, Haumann B, Biaggioni I. Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial. Clin Auton Res. 2021 Dec;31(6):699-711. doi: 10.1007/s10286-021-00827-0. Epub 2021 Oct 17.
- Lo A, Norcliffe-Kaufmann L, Vickery R, Bourdet D, Kanodia J. Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension. Clin Auton Res. 2021 Jun;31(3):395-403. doi: 10.1007/s10286-021-00800-x. Epub 2021 Mar 29.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Parkinsonian Disorders
- Basal Ganglia Diseases
- Movement Disorders
- Synucleinopathies
- Neurodegenerative Diseases
- Pathological Conditions, Anatomical
- Autonomic Nervous System Diseases
- Primary Dysautonomias
- Orthostatic Intolerance
- Parkinson Disease
- Hypotension
- Atrophy
- Multiple System Atrophy
- Shy-Drager Syndrome
- Hypotension, Orthostatic
- Pure Autonomic Failure
Other Study ID Numbers
- 0145
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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