Symptomatic Neurogenic Orthostatic Hypotension
Conditions
Keywords
Symptomatic Neurogenic Orthostatic Hypotension, symptomatic nOH, multiple system atrophy, MSA, Parkinson's disease, PD, pure autonomic failure, PAF, primary autonomic failure, SEQUOIA, ampreloxetine, low blood pressure, dizziness, fainting, blacking out, lightheadedness, norepinephrine, hypotension, Parkinsonism, TD-9855, Neurogenic Orthostatic Hypotension, nOH, 0145, 145, 169, 0169, TD9855
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 symptomatic nOH with up to 4 weeks of treatment.
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 symptomatic nOH. The study consists of 3 periods: (i) 4-week screening, (ii) 4-week randomized treatment, and (iii) 2-week follow up. The trial utilizes an operational design featuring the ability to conduct protocol required visits as either in clinic or remote visits (except Screening visit).
Interventions
DRUGampreloxetine
Oral tablet, QD
DRUGPlacebo
Oral tablet, QD
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Parallel assignment
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 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 documented impaired autonomic reflexes, including the Valsalva maneuver performed within 24 months from the date of randomization. * 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 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 within 7 days prior to V1. * Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1. * 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 (Columbia Suicide Severity Rating Scale) (Baseline/Screening Version) subject should be assessed by the rater for risk of suicide and the subject's appropriateness for inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4 | Baseline and Week 4 | OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale where each question 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. Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout. A mean negative change from baseline indicates a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4 | Baseline and Week 4 | OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale in which the composite score 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. A mean negative change from baseline indicates a better outcome. |
| Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4 | Baseline and Week 4 | OHDAS is an assessment of how low blood pressure symptoms affect daily life. OHDAS is a 4 item assessment in which the composite score 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. A mean negative change from baseline indicates a better outcome. |
| Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4 | Baseline and Week 4 | PGI-C was assessed using a 5-point scale where participants were asked to compare their current condition to their condition at baseline from 1 to 5, with 1 indicating the condition is very much improved and 5 indicating the condition is very much worse. These scores were analyzed in 2 categories: better and no change/worse. |
| Number of Participants Who Experienced at Least One Fall | Up to Week 4 | — |
Countries
Australia, Austria, Bulgaria, Canada, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Russia, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
195 participants were enrolled across 76 sites in Australia, Austria, Bulgaria, Canada, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Spain, Russia, Ukraine, United Kingdom and the United States.
Pre-assignment details
Overall, 194 randomized participants received at least one dose of study drug. Eight participants from one site were excluded from all analysis sets except the Randomized Analysis Set due to data integrity concerns.
Participants by arm
| Arm | Count |
|---|---|
| Ampreloxetine Participants received ampreloxetine at a dose of 10 mg once daily (QD) for 4 weeks.
Ampreloxetine: Oral tablet, QD | 98 |
| Placebo Participants received placebo once daily (QD) for 4 weeks. Placebo: Oral tablet, QD | 97 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Ampreloxetine | Placebo | Total |
|---|---|---|---|
| Age, Customized < 65 years | 28 Participants | 25 Participants | 53 Participants |
| Age, Customized ≥ 65 years | 70 Participants | 72 Participants | 142 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants | 91 Participants | 183 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 96 Participants | 94 Participants | 190 Participants |
| Sex: Female, Male Female | 37 Participants | 29 Participants | 66 Participants |
| Sex: Female, Male Male | 61 Participants | 68 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 96 | 0 / 90 |
| other Total, other adverse events | 42 / 96 | 38 / 90 |
| serious Total, serious adverse events | 4 / 96 | 2 / 90 |
Outcome results
Primary
Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4
OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale where each question 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. Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout. A mean negative change from baseline indicates a better outcome.
Time frame: Baseline and Week 4
Population: Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ampreloxetine | Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4 | -1.69 score on a scale | Standard Error 0.29 |
| Placebo | Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4 | -1.45 score on a scale | Standard Error 0.293 |
p-value: 0.57495% CI: [-1.05, 0.58]Mixed Model Repeated Measures
Secondary
Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4
OHDAS is an assessment of how low blood pressure symptoms affect daily life. OHDAS is a 4 item assessment in which the composite score 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. A mean negative change from baseline indicates a better outcome.
Time frame: Baseline and Week 4
Population: Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, with a valid composite OHDAS score at Week 4 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ampreloxetine | Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4 | -1.22 score on a scale | Standard Error 0.265 |
| Placebo | Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4 | -0.95 score on a scale | Standard Error 0.267 |
p-value: 0.48195% CI: [-1.01, 0.48]Mixed Model Repeated Measures
Secondary
Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4
OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale in which the composite score 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. A mean negative change from baseline indicates a better outcome.
Time frame: Baseline and Week 4
Population: Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, with a valid composite OHSA score at Week 4 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ampreloxetine | Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4 | -1.32 score on a scale | Standard Error 0.2 |
| Placebo | Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4 | -1.05 score on a scale | Standard Error 0.202 |
p-value: 0.33195% CI: [-0.84, 0.28]Mixed Model Repeated Measures
Secondary
Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4
PGI-C was assessed using a 5-point scale where participants were asked to compare their current condition to their condition at baseline from 1 to 5, with 1 indicating the condition is very much improved and 5 indicating the condition is very much worse. These scores were analyzed in 2 categories: better and no change/worse.
Time frame: Baseline and Week 4
Population: Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, who have available data were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ampreloxetine | Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4 | 49 Participants |
| Placebo | Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4 | 45 Participants |
p-value: 0.7495% CI: [-0.12, 0.17]Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Experienced at Least One Fall
Time frame: Up to Week 4
Population: Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, who have available data were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ampreloxetine | Number of Participants Who Experienced at Least One Fall | 33 Participants |
| Placebo | Number of Participants Who Experienced at Least One Fall | 22 Participants |
p-value: 0.090395% CI: [-0.02, 0.24]Cochran-Mantel-Haenszel