MSA, Parkinson's Disease (PD), Pure Autonomic Failure (PAF), Symptomatic Neurogenic Orthostatic Hypotension
Conditions
Keywords
Symptomatic Neurogenic Orthostatic Hypotension, symptomatic nOH, multiple symptom atrophy, MSA, Parkinson's disease, PD, pure autonomic failure, PAF, orthostatic hypotension, OH, REDWOOD, ampreloxetine, low blood pressure, dizziness, fainting, blacking out, lightheadedness, norepinephrine, hypotension, Neurogenic Orthostatic Hypotension, nOH, 170, 0170, 145, 0145, TD-9855, TD9855, Parkinsonism
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)).
Interventions
DRUGPlacebo
Oral tablet, QD
DRUGampreloxetine
Oral tablet, QD (Daily)
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Open Label Extension followed by Randomized Parallel Assignment
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period | 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. |
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
Participants were enrolled from February 2019 to November 2021. 203 participants were enrolled in the open label (OL) treatment period, including 170 participants from the 0169 study (NCT number: NCT03750552). 128 participants who completed the OL treatment period continued in the randomized withdrawal (RW) treatment period.
Participants by arm
| Arm | Count |
|---|---|
| OL Treatment Period: 0169 Placebo Rollover Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks. | 83 |
| OL Treatment Period: 0169 Ampreloxetine Rollover Participants who received ampreloxetine in study 0169, received 10 mg oral ampreloxetine QD for up to 16 weeks. | 85 |
| OL Treatment Period: De Novo Participants with symptomatic neurogenic orthostatic hypotension (nOH) who met all applicable study inclusion criteria and none of the applicable exclusion criteria, received 10 mg oral ampreloxetine QD for up to 16 weeks. These participants did not roll over from the 0169 study. | 32 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| OL Treatment Period (Week 1 to Week 16) | Adverse Event | 12 | 4 | 2 | 0 | 0 |
| OL Treatment Period (Week 1 to Week 16) | Failure to Meet Day 29 Continuation Criterion | 10 | 6 | 4 | 0 | 0 |
| OL Treatment Period (Week 1 to Week 16) | Miscellaneous | 3 | 1 | 1 | 0 | 0 |
| OL Treatment Period (Week 1 to Week 16) | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| OL Treatment Period (Week 1 to Week 16) | Study Terminated by Sponsor | 1 | 3 | 9 | 0 | 0 |
| OL Treatment Period (Week 1 to Week 16) | Withdrawal by Subject | 6 | 7 | 5 | 0 | 0 |
| RW Treatment Period (Week 16 to Week 24) | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| RW Treatment Period (Week 16 to Week 24) | Miscellaneous | 0 | 0 | 0 | 0 | 1 |
| RW Treatment Period (Week 16 to Week 24) | Study Terminated by Sponsor | 0 | 0 | 0 | 2 | 3 |
| RW Treatment Period (Week 16 to Week 24) | Withdrawal by Subject | 0 | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | OL Treatment Period: 0169 Placebo Rollover | OL Treatment Period: 0169 Ampreloxetine Rollover | OL Treatment Period: De Novo | Total |
|---|---|---|---|---|
| Age, Continuous | 68.2 years STANDARD_DEVIATION 9.35 | 68.2 years STANDARD_DEVIATION 9 | 69.0 years STANDARD_DEVIATION 7.97 | 68.4 years STANDARD_DEVIATION 8.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 76 Participants | 32 Participants | 185 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 0 Participants | 9 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 80 Participants | 83 Participants | 31 Participants | 194 Participants |
| Sex: Female, Male Female | 22 Participants | 30 Participants | 8 Participants | 60 Participants |
| Sex: Female, Male Male | 61 Participants | 55 Participants | 24 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 83 | 3 / 85 | 0 / 32 | 0 / 64 | 2 / 64 |
| other Total, other adverse events | 41 / 83 | 48 / 85 | 16 / 32 | 16 / 64 | 17 / 64 |
| serious Total, serious adverse events | 7 / 83 | 8 / 85 | 1 / 32 | 2 / 64 | 4 / 64 |
Outcome results
Primary
Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period
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.
Time frame: 6-week randomized withdrawal period (Week 16 to Week 22)
Population: RW Treatment Period Full Analysis Set: all randomized participants who received at least 1 dose of study medication (ampreloxetine or placebo) following randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RW Treatment Period: Placebo | Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period | 0.42 Proportion of participants | Standard Error 0.068 |
| RW Treatment Period: Ampreloxetine | Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period | 0.30 Proportion of participants | Standard Error 0.065 |
p-value: 0.19695% CI: [0.27, 1.29]Regression, Logistic