Multiple System Atrophy (MSA) With Orthostatic Hypotension
Pure Autonomic Failure
Parkinson Disease
Hypotension, Orthostatic
Orthostatic Hypotension
Pure Autonomic Failure With Orthostatic Hypotension
Parkinson Disease With Orthostatic Hypotension
Interventions
TD-9855
Placebo
Countries
United States
Protocol Section
Identification Module
NCT ID
NCT02705755
Obsolete or Duplicate NCT IDs
Not provided
Organization Study
0145
Secondary IDs
Not provided
Brief Title
TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH)
Official Title
A Phase 2 Study to Assess the Effect of TD-9855 in Subjects With Neurogenic Orthostatic Hypotension
Acronym
Not provided
Organization
Theravance BiopharmaINDUSTRY
Status Module
Record Verification Date
Feb 2022
Overall Recruitment Status or Expanded Access Status
Completed
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Not provided
Expanded Access Info
No
Start Date
Sep 9, 2017Actual
Primary Completion Date
Jul 24, 2018Actual
Completion Date
Nov 28, 2018Actual
First Submitted Date
Mar 7, 2016
First Submission Date that Met QC Criteria
Mar 7, 2016
First Posted Date
Mar 10, 2016Estimated
Results Waived
Not provided
Results First Submitted Date
Feb 24, 2022
Results First Submitted that Met QC Criteria
Aug 30, 2022
Results First Posted Date
Sep 26, 2022Actual
Certification/Extension (aka Delayed Results) First Submitted Date
Aug 8, 2019
Certification/Extension First Submitted that Passed QC Review
Aug 8, 2019
Certification/Extension First Posted Date
Aug 14, 2019Actual
Last Update Submitted Date
Aug 30, 2022
Last Update Posted Date
Sep 26, 2022Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Sponsor
Lead Sponsor
Theravance BiopharmaINDUSTRY
Collaborators
Not provided
Oversight Module
Has Data Monitoring Committee (DMC)
No
Is FDA Regulated Drug
Yes
Is FDA Regulated Device
No
Is Unapproved Device
Not provided
Pediatric Postmarket Surveillance of a Device Product
Not provided
Product Exported from US
Not provided
FDAAA801 Violation
Not provided
Description Module
Brief Summary
This multiple-center, 3-part, single-blind dose escalation (Part A), randomized, double-blind (Part B), and open-label multiple dose extension (Part C) study will be conducted in male and female subjects with neurogenic orthostatic hypotension to evaluate the effect of TD-9855 in improving symptoms of orthostatic intolerance.
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.
Conditions Module
Conditions
Neurogenic Orthostatic Hypotension
Multiple System Atrophy (MSA) With Orthostatic Hypotension
Pure Autonomic Failure
Parkinson Disease
Hypotension, Orthostatic
Orthostatic Hypotension
Pure Autonomic Failure With Orthostatic Hypotension
Parkinson Disease With Orthostatic Hypotension
Keywords
Neurogenic Orthostatic Hypotension (nOH)
Multiple System Atrophy (MSA)
Pure Autonomic Failure
Parkinson Disease(PD)
nOH
MSA
PD
PAF
Orthostatic Hypotension
ampreloxetine
TD-9855
Design Module
Study Type
Interventional
Number of References to an Expanded Access Study
Not provided
Expanded Access Types
Not provided
Patient Registry
Not provided
Target Follow-Up Duration
Not provided
Phases
Phase 2
Interventional Study Design
Allocation
Biospecimen
No data available
No data is available for this block.
Enrollment
34Actual
Arms/Interventions Module
Arm Groups
Label
Type
Description
Intervention Names
TD-9855 Part A
Experimental
Subjects will receive placebo and escalating single doses of TD-9855
Drug: TD-9855
Drug: Placebo
TD-9855 Part B
Experimental
Subjects will receive a single dose of TD-9855 or placebo.
Drug: TD-9855
Drug: Placebo
TD-9855 Part C
Experimental
Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.
Drug: TD-9855
Drug: Placebo
Interventions
Name
Type
Description
Arm Group Labels
Other Names
TD-9855
Drug
Administered orally.
TD-9855 Part A
TD-9855 Part B
TD-9855 Part C
Outcomes Module
Primary Outcomes
Measure
Description
Time Frame
Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP)
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
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
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.
Baseline to Week 4
Secondary Outcomes
Measure
Description
Time Frame
Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours
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.
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
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.
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.
34 participants were screened and all were enrolled and treated with study drug.
Recruitment Details
34 participants were enrolled across 6 sites in the United States between September 2017 and November 2018.
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
FG000
Part A: Dose Escalation (Within Group)
Part A of this study was a single blind within group dose escalation design. It started with placebo on Day 1 followed by a dose of 2.5 mg TD-9855 on Day 2, and proceeded to higher daily doses of TD-9855 up to maximum dose of 20 mg on Day 5 depending on safety, tolerability, and determination of a pressor effect.
There was a washout period of a minimum of 8 days up to 36 days between Part A and Part B and a minimum of 8 days between Part A and Part C.
Periods
Title
Milestones
Reasons Not Completed
Part A (6 Days)
Type
Comment
Milestone Data
STARTED
Each participant was titrated to their individual maximum tolerated dose.
Baseline Characteristics Module
Baseline Analysis Population Description
Not provided
Outcome Measures Module
Outcome Measures
Adverse Events Module
Frequency Threshold
0
More Info Module
Limitations and Caveats
Annotation Section
No data available
No data is available for this block.
Document Section
Large Document Module
Document Has No Statistical Analysis Plan (SAP)
Not provided
Uploaded Document Information
Type
Includes Protocol
Includes SAP
Includes ICF
Document Label
Document Date
Document Uploaded Date
Document File Name
Prot
Yes
No
No
Study Protocol
Nov 8, 2017
Feb 24, 2022
Derived Section
Miscellaneous Info Module
Version Holder
Jul 10, 2026
Removed Countries
Not provided
Submission Tracking
No data available
No data is available for this block.
Condition Browse Module
MeSH Terms
Intervention Browse Module
MeSH Terms
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Not provided
Primary Purpose
Treatment
Observational Model
Not provided
Time Perspective
Not provided
Masking Info
Masking
Single
Masking Description
Not provided
Who Masked
Participant
Placebo
Drug
Administered orally.
TD-9855 Part A
TD-9855 Part B
TD-9855 Part C
Baseline to a single time point between 6 to 8 hours post-dose
Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score
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
Part A: Change From Time-matched Placebo in Standing SBP
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
SBP was measured after 3 minutes of standing. Baseline was defined as the pre-dose measurement on Day 1 of Part B.
Baseline, 4 and 7 hours post-dose on Day 1
Part A: Change From Time-matched Placebo in Seated SBP
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)
Part B: Change From Baseline in Seated SBP
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
Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST)
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
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
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
Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS)
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.
Baseline to Day 169
Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score
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
Part C: Change From Baseline in Standing SBP
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
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
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.
Baseline to Day 169
Part C: Change From Baseline in Supine SBP to Seated SBP
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
Farmington Hills
Michigan
48334
United States
Theravance Biopharma Investigational Site
Berlin
New Jersey
08009
United States
Theravance Biopharma Investigational Site
New York
New York
10016
United States
Theravance Biopharma Investigational Site
Nashville
Tennessee
37232
United States
Theravance Biopharma Investigational Site
Dallas
Texas
75390
United States
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.
FG001
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
FG002
Part B: Randomized- TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
FG003
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
FG00034 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Received Placebo
FG00034 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Received 1 mg Study Drug
Participants who were enrolled prior to protocol amendment 2 received a starting dose of 1 mg TD-9855 as an oral solution on Day 2 of Part A and escalated to 10 mg. Beginning with protocol amendment 2, the starting dose was changed to 2.5 mg with dose escalation to 20 mg.
FG00017 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Received 2.5 mg Study Drug
FG00031 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Received 5 mg Study Drug
FG00029 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Received 10 mg Study Drug
FG00028 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Received 20 mg Study Drug
FG00013 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Rolled to Part B
FG00010 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Participants Who Rolled to Part C
FG00021 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
COMPLETED
FG00029 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
NOT COMPLETED
FG0005 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Type
Comment
Reasons
Adverse Event
FG0001 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Physician Decision
FG0003 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Withdrawal by Subject
FG0001 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Part B (1 Day)
Type
Comment
Milestone Data
STARTED
FG0000 subjects
FG0015 subjects
FG0025 subjectsEach participant received their individual maximum tolerated dose from Part A.
FG0030 subjects
Received Study Drug
FG0000 subjects
FG0015 subjects
FG0025 subjects
FG0030 subjects
COMPLETED
FG0000 subjects
FG0015 subjects
FG0025 subjects
FG0030 subjects
NOT COMPLETED
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
Part C (20 Weeks)
Type
Comment
Milestone Data
STARTED
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG00321 subjects
Received Study Drug
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG00321 subjects
COMPLETED
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG00311 subjects
NOT COMPLETED
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG00310 subjects
Type
Comment
Reasons
Physician Decision
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
BG000
All Study Participants
All study participants from Parts A, B, and C. Each part of the study is reported as a row in each of the Baseline Measures.
Denominators
Units
Counts
Participants
BG00034
Baseline Measures
Title
Description
Population Description
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Denominator Units Selected
Denominators
Classes
Age, Continuous
The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Mean
Standard Deviation
years
Title
Denominators
Categories
Part A: Dose Escalation (Within Group)
ParticipantsBG00034
Title
Measurements
BG00065.8± 7.94
Part B: Randomized - Placebo
ParticipantsBG000
Sex: Female, Male
The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Count of Participants
Participants
Title
Denominators
Categories
Part A: Part A: Dose Escalation (Within Group)
ParticipantsBG00034
Title
Measurements
Female
BG000
Ethnicity (NIH/OMB)
Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Count of Participants
Participants
Title
Denominators
Categories
Part A: Dose Escalation (Within Group)
ParticipantsBG00034
Title
Measurements
Hispanic or Latino
BG000
Race (NIH/OMB)
Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Count of Participants
Participants
Title
Denominators
Categories
Part A: Dose Escalation (Within Group)
ParticipantsBG00034
Title
Measurements
American Indian or Alaska Native
BG000
Type
Title
Description
Population Description
Reporting Status
Anticipated Posting Date
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Time Frame
Units Analyzed
Denominator Units Selected
Arm/Group Information
Denominators
Classes
Analyses
Primary
Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP)
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).
Intent-to-treat (ITT) analysis set - All analyzable participants who received placebo on Day 1 of Part A.
Posted
Mean
Standard Deviation
millimeter of mercury (mmHg)
7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
ID
Title
Description
OG000
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
OG001
Part A: TD-9855 2.5 mg
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
OG002
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
OG003
Part A: TD-9855 10 mg
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
OG004
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
Units
Counts
Participants
OG00017
OG00130
OG00228
OG003
Title
Denominators
Categories
Title
Measurements
OG0000.2± 18.58
OG001-1.8± 20.27
OG002-3.4± 16.50
OG003
Primary
Part B: Change From Baseline in Seated SBP
Baseline was defined as the pre-dose measurement on Day 1 of Part B.
ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
Posted
Mean
Standard Deviation
mmHg
Baseline and 7 hours post-dose on Day 1
ID
Title
Description
OG000
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
OG001
Part B: Randomized- TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
Units
Primary
Part C: Change From Baseline in Likert Scale Score at 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.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
score on a scale
Baseline to Week 4
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Participants
Secondary
Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours
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.
ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A. All analyzable participants who received any amount of placebo or TD-9855 in Part B.
Posted
Mean
Standard Deviation
score on a scale
Baseline to a single time point between 6 to 8 hours post-dose
ID
Title
Description
OG000
Part A: Placebo
Participants received a placebo matching TD-9855 on Day 1 of the Part A treatment period.
OG001
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
OG002
Part A: TD-9855 2.5 mg
Secondary
Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score
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.
ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A. All analyzable participants who received any amount of placebo or TD-9855 in Part B.
Posted
Mean
Standard Deviation
score on a scale
Baseline to a single time point between 6 to 8 hours post-dose
ID
Title
Description
OG000
Part A: Placebo
Participants received a placebo matching TD-9855 on Day 1 of the Part A treatment period.
OG001
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
Secondary
Part A: Change From Time-matched Placebo in Standing SBP
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.
ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A.
Posted
Mean
Standard Deviation
mmHg
4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
ID
Title
Description
OG000
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
OG001
Part A: TD-9855 2.5 mg
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
OG002
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
OG003
Secondary
Part B: Change From Baseline in Standing SBP
SBP was measured after 3 minutes of standing. Baseline was defined as the pre-dose measurement on Day 1 of Part B.
ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
Posted
Mean
Standard Deviation
mmHg
Baseline, 4 and 7 hours post-dose on Day 1
ID
Title
Description
OG000
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
OG001
Part B: Randomized- TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
Secondary
Part A: Change From Time-matched Placebo in Seated SBP
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).
ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A.
Posted
Mean
Standard Deviation
mmHg
4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing)
ID
Title
Description
OG000
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
OG001
Part A: TD-9855 2.5 mg
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
OG002
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
OG003
Part A: TD-9855 10 mg
Secondary
Part B: Change From Baseline in Seated SBP
Baseline was defined as the pre-dose measurement on Day 1 of Part B.
ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
Posted
Mean
Standard Deviation
mmHg
Baseline and 4, 7, 9 and 12 hours post-dose on Day 1
ID
Title
Description
OG000
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
OG001
Part B: Randomized- TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
Secondary
Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST)
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.
ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A.
Posted
Mean
Standard Deviation
minutes
4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
ID
Title
Description
OG000
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
OG001
Part A: TD-9855 2.5 mg
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
Secondary
Part B: Change From Baseline in Duration of Standing During the OST
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.
ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
Posted
Mean
Standard Deviation
minutes
Baseline and 7 hours post-dose on Day 1
ID
Title
Description
OG000
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
OG001
Part B: Randomized- TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
Secondary
Part C: Change From Baseline in the Composite OHSA Score
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.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
score on a scale
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Participants
Secondary
Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS)
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.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
score on a scale
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Secondary
Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score
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.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
score on a scale
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Secondary
Part C: Change From Baseline in Standing SBP
SBP was measured after 3 minutes of standing. Baseline was defined as the pre-lunch measurement on Day 1.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
mmHg
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Participants
OG000
Secondary
Part C: Change From Baseline in Seated SBP
Baseline was defined as the pre-breakfast measurement on Day 1.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
mmHg
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Participants
OG000
Secondary
Part C: Change From Baseline in Duration of Standing During the OST
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.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
minutes
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Participants
Secondary
Part C: Change From Baseline in Supine SBP to Seated SBP
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.
ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
Posted
Mean
Standard Deviation
mmHg
Baseline to Day 169
ID
Title
Description
OG000
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
Units
Counts
Participants
OG000
Time Frame
Part A: Day 1 to Day 6 of Part A treatment period, plus 30 days. Part B: Day 1 of Part B treatment period, plus 30 days. Part C: Day 1 to Day 169 of Part C treatment period.
Description
Not provided
All-Cause Mortality Comment
Not provided
Arm/Groups
ID
Title
Description
Deaths (Affected)
Deaths (At Risk)
Serious Events (Affected)
Serious Events (At Risk)
Other Events (Affected)
Other Events (At Risk)
EG000
Part A: Placebo
Participants received a placebo matching TD-9855 on Day 1 of the Part A treatment period.
0
34
0
34
7
34
EG001
Part A: TD-9855 1 mg
Participants who were enrolled prior to protocol amendment 2 received 1 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period.
0
17
0
17
4
17
EG002
Part A: TD-9855 2.5 mg
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
0
31
0
31
5
31
EG003
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
0
29
0
29
3
29
EG004
Part A: TD-9855 10 mg
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
0
28
0
28
6
28
EG005
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
0
13
0
13
1
13
EG006
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
0
5
0
5
0
5
EG007
Part B: Randomized - TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
0
5
0
5
1
5
EG008
Part C: Dose Extension
Part C of this study was an open-label dose extension period. Participants who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 daily for up to 20 weeks in Part C.
The dose of TD-9855 administered on Day 1 in Part C, following the washout period, was equal to 50% (or lower) of the highest tolerated dose administered during Part A. After Day 29, dose increases were made at the discretion of the investigator.
0
21
5
21
18
21
Serious Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Urinary tract infection
Infections and infestations
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG0030 affected29 at risk
EG0040 affected28 at risk
EG0050 affected13 at risk
EG0060 affected5 at risk
EG0070 affected5 at risk
EG0083 affected21 at risk
Jaw fracture
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Meniscus injury
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Pain in extremity
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Other Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Atrial fibrillation
Cardiac disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG0030 affected29 at risk
EG0041 affected28 at risk
EG0050 affected13 at risk
EG0060 affected5 at risk
EG0070 affected5 at risk
EG0080 affected21 at risk
Palpitations
Cardiac disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Ear pain
Ear and labyrinth disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Photopsia
Eye disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0011 affected17 at risk
EG0020 affected31 at risk
EG003
Constipation
Gastrointestinal disorders
MedDRA 18.1
Systematic Assessment
EG0002 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Nausea
Gastrointestinal disorders
MedDRA 18.1
Systematic Assessment
EG0001 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Fatigue
General disorders
MedDRA 18.1
Systematic Assessment
EG0001 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Feeling jittery
General disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Oedema
General disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0011 affected17 at risk
EG0020 affected31 at risk
EG003
Urinary tract infection
Infections and infestations
MedDRA 18.1
Systematic Assessment
EG0001 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Oral herpes
Infections and infestations
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0021 affected31 at risk
EG003
Muscle strain
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Musculoskeletal stiffness
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Myalgia
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0021 affected31 at risk
EG003
Headache
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0002 affected34 at risk
EG0010 affected17 at risk
EG0021 affected31 at risk
EG003
Loss of consciousness
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0001 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Paraesthesia
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0001 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Hallucination, visual
Psychiatric disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0021 affected31 at risk
EG003
Impulse-control disorder
Psychiatric disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0011 affected17 at risk
EG0020 affected31 at risk
EG003
Oropharyngeal pain
Respiratory, thoracic and mediastinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0021 affected31 at risk
EG003
Seborrhoea
Skin and subcutaneous tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0011 affected17 at risk
EG0020 affected31 at risk
EG003
Skin lesion
Skin and subcutaneous tissue disorders
MedDRA 18.1
Systematic Assessment
EG0001 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Orthostatic hypotension
Vascular disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Diplopia
Eye disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Vision blurred
Eye disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Dyspepsia
Gastrointestinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Gastrooesophageal reflux disease
Gastrointestinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Vomiting
Gastrointestinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Chest discomfort
General disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Asthenia
General disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Peripheral swelling
General disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Bronchitis
Infections and infestations
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Localised infection
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Laceration
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Ear canal injury
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Fall
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Joint injury
Injury, poisoning and procedural complications
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Blood pressure increased
Investigations
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Urine analysis abnormal
Investigations
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Musculoskeletal pain
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Back pain
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Muscular weakness
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Neck pain
Musculoskeletal and connective tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Dizziness
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Syncope
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Hypoaesthesia
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Unresponsive to stimuli
Nervous system disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Haematuria
Renal and urinary disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Cough
Respiratory, thoracic and mediastinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Dyspnoea
Respiratory, thoracic and mediastinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Sleep apnoea syndrome
Respiratory, thoracic and mediastinal disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Erythema
Skin and subcutaneous tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Solar lentigo
Skin and subcutaneous tissue disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Hypertension
Vascular disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Deep vein thrombosis
Vascular disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Flushing
Vascular disorders
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Localised infection
Infections and infestations
MedDRA 18.1
Systematic Assessment
EG0000 affected34 at risk
EG0010 affected17 at risk
EG0020 affected31 at risk
EG003
Part B of the study was discontinued in protocol amendment 2, however details regarding Part B are still included in this summary.
Multiple system atrophy (MSA) with orthostatic hypotension
D054970
Pure Autonomic Failure
D010300
Parkinson Disease
D007024
Hypotension, Orthostatic
D019578
Multiple System Atrophy
Ancestor Terms
ID
Term
D054969
Primary Dysautonomias
D001342
Autonomic Nervous System Diseases
D009422
Nervous System Diseases
D020734
Parkinsonian Disorders
D001480
Basal Ganglia Diseases
D001927
Brain Diseases
D002493
Central Nervous System Diseases
D009069
Movement Disorders
D000080874
Synucleinopathies
D019636
Neurodegenerative Diseases
D054971
Orthostatic Intolerance
D007022
Hypotension
D014652
Vascular Diseases
D002318
Cardiovascular Diseases
Browse Leaves
Not provided
Browse Branches
Not provided
ID
Term
C000601820
ampreloxetine
Ancestor Terms
Not provided
Browse Leaves
Not provided
Browse Branches
Not provided
2 subjects
Adverse Event
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0036 subjects
Withdrawal by Subject
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0032 subjects
5
Title
Measurements
BG00065.2± 8.98
Part B: Randomized - TD-9855
ParticipantsBG0005
Title
Measurements
BG00066.4± 5.22
Part C: Dose Extension
ParticipantsBG00021
Title
Measurements
BG00064.1± 7.91
12
Male
BG00022
Part B: Randomized - Placebo
ParticipantsBG0005
Title
Measurements
Female
BG0002
Male
BG0003
Part B: Randomized - TD-9855
ParticipantsBG0005
Title
Measurements
Female
BG0002
Male
BG0003
Part C: Dose Extension
ParticipantsBG00021
Title
Measurements
Female
BG0009
Male
BG00012
3
Not Hispanic or Latino
BG00030
Unknown or Not Reported
BG0001
Part B: Randomized - Placebo
ParticipantsBG0005
Title
Measurements
Hispanic or Latino
BG0001
Not Hispanic or Latino
BG0004
Unknown or Not Reported
BG0000
Part B: Randomized - TD-9855
ParticipantsBG0005
Title
Measurements
Hispanic or Latino
BG0000
Not Hispanic or Latino
BG0005
Unknown or Not Reported
BG0000
Part C: Dose Extension
ParticipantsBG00021
Title
Measurements
Hispanic or Latino
BG0002
Not Hispanic or Latino
BG00018
Unknown or Not Reported
BG0001
0
Asian
BG0001
Native Hawaiian or Other Pacific Islander
BG0000
Black or African American
BG0002
White
BG00031
More than one race
BG0000
Unknown or Not Reported
BG0000
Part B: Randomized - Placebo
ParticipantsBG0005
Title
Measurements
American Indian or Alaska Native
BG0000
Asian
BG0001
Native Hawaiian or Other Pacific Islander
BG0000
Black or African American
BG0000
White
BG0004
More than one race
BG0000
Unknown or Not Reported
BG0000
Part B: Randomized - TD-9855
ParticipantsBG0005
Title
Measurements
American Indian or Alaska Native
BG0000
Asian
BG0000
Native Hawaiian or Other Pacific Islander
BG0000
Black or African American
BG0000
White
BG0005
More than one race
BG0000
Unknown or Not Reported
BG0000
Part C: Dose Extension
ParticipantsBG00021
Title
Measurements
American Indian or Alaska Native
BG0000
Asian
BG0001
Native Hawaiian or Other Pacific Islander
BG0000
Black or African American
BG0002
White
BG00018
More than one race
BG0000
Unknown or Not Reported
BG0000
28
OG00413
-2.9
± 21.53
OG004-7.3± 18.86
Counts
Participants
OG0005
OG0015
Title
Denominators
Categories
Title
Measurements
OG0000.30± 27.655
OG0019.00± 13.139
OG00016
Title
Denominators
Categories
Title
Measurements
OG000-2.4± 4.54
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
OG003
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
OG004
Part A: TD-9855 10 mg
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
OG005
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
OG006
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
OG007
Part B: Randomized - TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
Units
Counts
Participants
OG00033
OG00116
OG00229
OG00327
OG00427
OG00513
OG0065
OG0075
Title
Denominators
Categories
Title
Measurements
OG000-0.6± 2.46
OG001-0.9± 4.08
OG002-1.4± 3.61
OG003-1.3± 3.59
OG004-2.0± 3.66
OG005-2.2± 3.19
OG006-1.6± 3.44
OG007-1.8± 2.28
OG002
Part A: TD-9855 2.5 mg
Participants received 2.5 mg of TD-9855 as an oral solution on Day 2 of the Part A treatment period (Day 3 if enrolled prior to protocol amendment 2).
OG003
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
OG004
Part A: TD-9855 10 mg
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
OG005
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
OG006
Part B: Randomized - Placebo
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of placebo on Day 1 of the treatment period.
OG007
Part B: Randomized - TD-9855
Part B of this study followed a randomized, double-blind, placebo-controlled, parallel design at the dose level of TD-9855 determined to have a pressor effect for a given participant in Part A. Participants from Part A were rolled over into Part B.
Following the washout period after Part A, participants were randomized to receive a single dose of their previously tolerated dose of TD-9855 on Day 1 of the treatment period.
Units
Counts
Participants
OG00033
OG00116
OG00229
OG00327
OG00427
OG00513
OG0065
OG0075
Title
Denominators
Categories
Title
Measurements
OG000-0.07± 1.808
OG001-0.30± 2.157
OG002-0.64± 1.730
OG003-0.78± 2.232
OG004-1.22± 2.625
OG005-1.31± 2.340
OG006-1.0± 2.64
OG007-0.3± 1.74
Part A: TD-9855 10 mg
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
OG004
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
Units
Counts
Participants
OG0007
OG00113
OG00212
OG00311
OG0045
Title
Denominators
Categories
4 Hours Post-dose
ParticipantsOG0006
ParticipantsOG00113
ParticipantsOG00212
ParticipantsOG00311
ParticipantsOG0045
Title
Measurements
OG000-3.8± 8.80
OG0018.6± 14.13
OG0026.8± 15.85
OG003
7 Hours Post-dose
ParticipantsOG0007
ParticipantsOG00112
ParticipantsOG00210
ParticipantsOG00310
Units
Counts
Participants
OG0003
OG0012
Title
Denominators
Categories
4 Hours Post-dose
ParticipantsOG0002
ParticipantsOG0012
Title
Measurements
OG000-5.0± 8.49
OG00120.5± 2.12
7 Hours Post-dose
ParticipantsOG0003
ParticipantsOG0012
Title
Measurements
OG000-4.0± 12.00
OG001
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
OG004
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
Units
Counts
Participants
OG00017
OG00131
OG00228
OG00328
OG00413
Title
Denominators
Categories
4 Hours Post-dose
ParticipantsOG00017
ParticipantsOG00131
ParticipantsOG00228
ParticipantsOG00328
ParticipantsOG00413
Title
Measurements
OG000-3.2± 15.89
OG0012.4± 15.24
OG0025.9± 21.85
OG003
7 Hours Post-dose
ParticipantsOG00017
ParticipantsOG00130
ParticipantsOG00228
ParticipantsOG00328
9 Hours Post-dose
ParticipantsOG00017
ParticipantsOG00129
ParticipantsOG00228
ParticipantsOG00328
12 Hours Post-dose
ParticipantsOG00016
ParticipantsOG00128
ParticipantsOG00227
ParticipantsOG00327
Units
Counts
Participants
OG0005
OG0015
Title
Denominators
Categories
4 Hours Post-dose
Title
Measurements
OG000-9.70± 26.397
OG00111.20± 26.407
7 Hours Post-dose
Title
Measurements
OG0000.30± 27.665
OG0019.00± 13.139
9 Hours Post-dose
Title
Measurements
OG0006.70± 29.668
OG0017.40± 19.415
12 Hours Post-dose
Title
Measurements
OG0009.90± 32.809
OG001-6.90± 43.118
OG002
Part A: TD-9855 5 mg
Participants received 5 mg of TD-9855 as an oral solution on Day 3 of the Part A treatment period (Day 4 if enrolled prior to protocol amendment 2).
OG003
Part A: TD-9855 10 mg
Participants received 10 mg of TD-9855 as an oral solution on Day 4 of the Part A treatment period (Day 5 if enrolled prior to protocol amendment 2).
OG004
Part A: TD-9855 20 mg
Participants received 20 mg of TD-9855 as an oral solution on Day 5 of the Part A treatment period. Participants who were enrolled prior to protocol amendment 2 were not up-titrated to the 20 mg dosing level.
Units
Counts
Participants
OG00017
OG00131
OG00228
OG00328
OG00413
Title
Denominators
Categories
4 Hours Post-dose
ParticipantsOG00017
ParticipantsOG00131
ParticipantsOG00228
ParticipantsOG00328
ParticipantsOG00413
Title
Measurements
OG0000.698± 3.1357
OG0010.799± 2.7898
OG0021.085± 3.4188
OG003
7 Hours Post-dose
ParticipantsOG00016
ParticipantsOG00129
ParticipantsOG00227
ParticipantsOG00327
Units
Counts
Participants
OG0005
OG0015
Title
Denominators
Categories
Title
Measurements
OG0003.38± 5.275
OG0010.15± 0.5080
Group IDs
Group Description
Statistical Method
Statistical Comment
P-Value
P-Value Comment
Parameter Type
Parameter Value
Dispersion Type
Dispersion Value
Confidence Interval Sides
Confidence Interval %
CI Lower Limit
CI Upper Limit
CI Lower Limit Comment
CI Upper Limit Comment
Estimate Comment
Tested Non-Inferiority
Non-Inferiority Type
Non-Inferiority Comment
Other Analysis Description
OG000
OG001
Least squares mean differences were calculated based on a repeated-measures mixed-effect model with change from baseline at different time points as the dependent variable, the treatment group (TD-9855 or placebo), time point, baseline and the interaction between the treatment group and time point as fixed factors. A compound symmetry was used as the variance-covariance structure.
Repeated-measures Mixed-effect Model
0.0399
P-values were reported without multiplicity adjustment.