Hypotension, Orthostatic, Multiple System Atrophy (MSA) With Orthostatic Hypotension, Neurogenic Orthostatic Hypotension, Orthostatic Hypotension, Parkinson Disease, Parkinson Disease With Orthostatic Hypotension, Pure Autonomic Failure, Pure Autonomic Failure With Orthostatic Hypotension
Conditions
Keywords
Neurogenic Orthostatic Hypotension (nOH), Multiple System Atrophy (MSA), Pure Autonomic Failure, Parkinson Disease(PD), nOH, MSA, PD, PAF, Orthostatic Hypotension, ampreloxetine, TD-9855
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.
Interventions
DRUGTD-9855
Administered orally.
DRUGPlacebo
Administered orally.
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing) | Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1). |
| Part B: Change From Baseline in Seated SBP | Baseline and 7 hours post-dose on Day 1 | Baseline was defined as the pre-dose measurement on Day 1 of Part B. |
| Part C: Change From Baseline in Likert Scale Score at Week 4 | Baseline to Week 4 | The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A higher score indicates a worse outcome. Baseline was defined as the pre-lunch measurement on Day -1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Change From Baseline in Standing SBP | Baseline, 4 and 7 hours post-dose on Day 1 | SBP was measured after 3 minutes of standing. Baseline was defined as the pre-dose measurement on Day 1 of Part B. |
| Part A: Change From Time-matched Placebo in Seated SBP | 4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing) | Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1). |
| Part B: Change From Baseline in Seated SBP | Baseline and 4, 7, 9 and 12 hours post-dose on Day 1 | Baseline was defined as the pre-dose measurement on Day 1 of Part B. |
| Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing) | Blood pressure (BP) and heart rate (HR) measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1) of Part A. |
| Part B: Change From Baseline in Duration of Standing During the OST | Baseline and 7 hours post-dose on Day 1 | BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Baseline was defined as the predose measurement on Day 1 of Part B. |
| Part C: Change From Baseline in the Composite OHSA Score | Baseline to Day 169 | The OHSA is made up of a 6-item symptoms assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting cannot be done for other reasons. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. Baseline was defined as the pre-lunch measurement on Day -1. |
| Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | Baseline to a single time point between 6 to 8 hours post-dose | The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A higher score indicates a worse outcome. Baseline was defined as the pre-dose measurement on Day 1 for Part A and Part B. Data was collected a one point between 6 and 8 hours post-dose. |
| Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Baseline to Day 169 | The OHQ is a 2-component questionnaire made up of 6-item symptoms assessment referred to as OHSA, and a 4-item daily activity assessment referred to as the OHDAS. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting cannot be done for other reasons. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. The composite OHDAS score is the average of the response scores (for non-missing data) to the 4 questions of OHDAS. The OHQ composite score is the average of the OHSA and OHDAS composite scores. Baseline was defined as the pre-lunch measurement on Day -1. |
| Part C: Change From Baseline in Standing SBP | Baseline to Day 169 | SBP was measured after 3 minutes of standing. Baseline was defined as the pre-lunch measurement on Day 1. |
| Part C: Change From Baseline in Seated SBP | Baseline to Day 169 | Baseline was defined as the pre-breakfast measurement on Day 1. |
| Part C: Change From Baseline in Duration of Standing During the OST | Baseline to Day 169 | BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Baseline was defined as the pre-breakfast measurement on Day 1. |
| Part C: Change From Baseline in Supine SBP to Seated SBP | Baseline to Day 169 | 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. |
| Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Baseline to Day 169 | The OHDAS is made up of a 4-item daily activity assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting cannot be done for other reasons. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHDAS score is the average of the response scores (for non-missing data) to the 4 questions of OHDAS. Baseline was defined as the pre-lunch measurement on Day -1. |
| Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | Baseline to a single time point between 6 to 8 hours post-dose | The OHSA is made up of a 6-item symptoms assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. A reduction in composite score indicates an improvement in symptoms. Baseline was defined as the pre-dose measurement on Day 1 for Part A and Part B. Data was collected a one point between 6 and 8 hours post-dose. |
| Part A: Change From Time-matched Placebo in Standing SBP | 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing) | Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1). SBP was measured after 5 minutes of standing. |
Countries
United States
Participant flow
Recruitment details
34 participants were enrolled across 6 sites in the United States between September 2017 and November 2018.
Pre-assignment details
34 participants were screened and all were enrolled and treated with study drug.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A (6 Days) | Adverse Event | 1 | 0 | 0 | 0 |
| Part A (6 Days) | Physician Decision | 3 | 0 | 0 | 0 |
| Part A (6 Days) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Part C (20 Weeks) | Adverse Event | 0 | 0 | 0 | 6 |
| Part C (20 Weeks) | Physician Decision | 0 | 0 | 0 | 2 |
| Part C (20 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous Part A: Dose Escalation (Within Group) | 65.8 years STANDARD_DEVIATION 7.94 |
| Age, Continuous Part B: Randomized - Placebo | 65.2 years STANDARD_DEVIATION 8.98 |
| Age, Continuous Part B: Randomized - TD-9855 | 66.4 years STANDARD_DEVIATION 5.22 |
| Age, Continuous Part C: Dose Extension | 64.1 years STANDARD_DEVIATION 7.91 |
| Ethnicity (NIH/OMB) Part A: Dose Escalation (Within Group) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Part A: Dose Escalation (Within Group) Not Hispanic or Latino | 30 Participants |
| Ethnicity (NIH/OMB) Part A: Dose Escalation (Within Group) Unknown or Not Reported | 1 Participants |
| Ethnicity (NIH/OMB) Part B: Randomized - Placebo Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Part B: Randomized - Placebo Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Part B: Randomized - Placebo Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Part B: Randomized - TD-9855 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Part B: Randomized - TD-9855 Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Part B: Randomized - TD-9855 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Part C: Dose Extension Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Part C: Dose Extension Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Part C: Dose Extension Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) Asian | 1 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) Black or African American | 2 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) More than one race | 0 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Part A: Dose Escalation (Within Group) White | 31 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo Asian | 1 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo Black or African American | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo More than one race | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - Placebo White | 4 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 Asian | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 Black or African American | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 More than one race | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Part B: Randomized - TD-9855 White | 5 Participants |
| Race (NIH/OMB) Part C: Dose Extension American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Part C: Dose Extension Asian | 1 Participants |
| Race (NIH/OMB) Part C: Dose Extension Black or African American | 2 Participants |
| Race (NIH/OMB) Part C: Dose Extension More than one race | 0 Participants |
| Race (NIH/OMB) Part C: Dose Extension Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Part C: Dose Extension Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Part C: Dose Extension White | 18 Participants |
| Sex: Female, Male Part A: Part A: Dose Escalation (Within Group) Female | 12 Participants |
| Sex: Female, Male Part A: Part A: Dose Escalation (Within Group) Male | 22 Participants |
| Sex: Female, Male Part B: Randomized - Placebo Female | 2 Participants |
| Sex: Female, Male Part B: Randomized - Placebo Male | 3 Participants |
| Sex: Female, Male Part B: Randomized - TD-9855 Female | 2 Participants |
| Sex: Female, Male Part B: Randomized - TD-9855 Male | 3 Participants |
| Sex: Female, Male Part C: Dose Extension Female | 9 Participants |
| Sex: Female, Male Part C: Dose Extension Male | 12 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 17 | 0 / 31 | 0 / 29 | 0 / 28 | 0 / 13 | 0 / 5 | 0 / 5 | 0 / 21 |
| other Total, other adverse events | 7 / 34 | 4 / 17 | 5 / 31 | 3 / 29 | 6 / 28 | 1 / 13 | 0 / 5 | 1 / 5 | 18 / 21 |
| serious Total, serious adverse events | 0 / 34 | 0 / 17 | 0 / 31 | 0 / 29 | 0 / 28 | 0 / 13 | 0 / 5 | 0 / 5 | 5 / 21 |
Outcome results
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).
Time frame: 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
Population: Intent-to-treat (ITT) analysis set - All analyzable participants who received placebo on Day 1 of Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | 0.2 millimeter of mercury (mmHg) | Standard Deviation 18.58 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | -1.8 millimeter of mercury (mmHg) | Standard Deviation 20.27 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | -3.4 millimeter of mercury (mmHg) | Standard Deviation 16.5 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | -2.9 millimeter of mercury (mmHg) | Standard Deviation 21.53 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | -7.3 millimeter of mercury (mmHg) | Standard Deviation 18.86 |
Primary
Part B: Change From Baseline in Seated SBP
Baseline was defined as the pre-dose measurement on Day 1 of Part B.
Time frame: Baseline and 7 hours post-dose on Day 1
Population: ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Seated SBP | 0.30 mmHg | Standard Deviation 27.655 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Seated SBP | 9.00 mmHg | Standard Deviation 13.139 |
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.
Time frame: Baseline to Week 4
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Likert Scale Score at Week 4 | -2.4 score on a scale | Standard Deviation 4.54 |
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.
Time frame: Baseline to a single time point between 6 to 8 hours post-dose
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TD-9855 1 mg | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -0.6 score on a scale | Standard Deviation 2.46 |
| Part A: TD-9855 2.5 mg | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -0.9 score on a scale | Standard Deviation 4.08 |
| Part A: TD-9855 5 mg | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -1.4 score on a scale | Standard Deviation 3.61 |
| Part A: TD-9855 10 mg | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -1.3 score on a scale | Standard Deviation 3.59 |
| Part A: TD-9855 20 mg | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -2.0 score on a scale | Standard Deviation 3.66 |
| Part A: TD-9855 20 mg | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -2.2 score on a scale | Standard Deviation 3.19 |
| Part B: Randomized - Placebo | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -1.6 score on a scale | Standard Deviation 3.44 |
| Part B: Randomized - TD-9855 | Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | -1.8 score on a scale | Standard Deviation 2.28 |
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.
Time frame: Baseline to a single time point between 6 to 8 hours post-dose
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TD-9855 1 mg | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -0.07 score on a scale | Standard Deviation 1.808 |
| Part A: TD-9855 2.5 mg | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -0.30 score on a scale | Standard Deviation 2.157 |
| Part A: TD-9855 5 mg | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -0.64 score on a scale | Standard Deviation 1.73 |
| Part A: TD-9855 10 mg | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -0.78 score on a scale | Standard Deviation 2.232 |
| Part A: TD-9855 20 mg | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -1.22 score on a scale | Standard Deviation 2.625 |
| Part A: TD-9855 20 mg | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -1.31 score on a scale | Standard Deviation 2.34 |
| Part B: Randomized - Placebo | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -1.0 score on a scale | Standard Deviation 2.64 |
| Part B: Randomized - TD-9855 | Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | -0.3 score on a scale | Standard Deviation 1.74 |
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.
Time frame: 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
Population: ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 4 Hours Post-dose | 0.698 minutes | Standard Deviation 3.1357 |
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 7 Hours Post-dose | 0.747 minutes | Standard Deviation 3.3856 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 4 Hours Post-dose | 0.799 minutes | Standard Deviation 2.7898 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 7 Hours Post-dose | 1.343 minutes | Standard Deviation 2.7847 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 4 Hours Post-dose | 1.085 minutes | Standard Deviation 3.4188 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 7 Hours Post-dose | 0.952 minutes | Standard Deviation 3.6232 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 7 Hours Post-dose | 0.986 minutes | Standard Deviation 4.3645 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 4 Hours Post-dose | 1.579 minutes | Standard Deviation 3.5527 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 4 Hours Post-dose | 1.081 minutes | Standard Deviation 2.8553 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | 7 Hours Post-dose | 1.159 minutes | Standard Deviation 2.8264 |
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).
Time frame: 4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing)
Population: ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Seated SBP | 4 Hours Post-dose | -3.2 mmHg | Standard Deviation 15.89 |
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Seated SBP | 7 Hours Post-dose | 0.2 mmHg | Standard Deviation 18.58 |
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Seated SBP | 9 Hours Post-dose | 4.1 mmHg | Standard Deviation 19.08 |
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Seated SBP | 12 Hours Post-dose | 2.4 mmHg | Standard Deviation 22.2 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 4 Hours Post-dose | 2.4 mmHg | Standard Deviation 15.24 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 12 Hours Post-dose | -1.4 mmHg | Standard Deviation 17.44 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 7 Hours Post-dose | -1.8 mmHg | Standard Deviation 20.27 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 9 Hours Post-dose | 0.7 mmHg | Standard Deviation 18.9 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 12 Hours Post-dose | 0.4 mmHg | Standard Deviation 19.86 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 7 Hours Post-dose | -3.4 mmHg | Standard Deviation 16.5 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 9 Hours Post-dose | 5.5 mmHg | Standard Deviation 21.14 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Seated SBP | 4 Hours Post-dose | 5.9 mmHg | Standard Deviation 21.85 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Seated SBP | 4 Hours Post-dose | 4.9 mmHg | Standard Deviation 20.14 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Seated SBP | 7 Hours Post-dose | -2.9 mmHg | Standard Deviation 21.53 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Seated SBP | 12 Hours Post-dose | 7.4 mmHg | Standard Deviation 24.88 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Seated SBP | 9 Hours Post-dose | 2.5 mmHg | Standard Deviation 20.85 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Seated SBP | 12 Hours Post-dose | -2.5 mmHg | Standard Deviation 14.42 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Seated SBP | 9 Hours Post-dose | 9.8 mmHg | Standard Deviation 26.48 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Seated SBP | 7 Hours Post-dose | -7.3 mmHg | Standard Deviation 18.86 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Seated SBP | 4 Hours Post-dose | 0.7 mmHg | Standard Deviation 17.4 |
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.
Time frame: 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
Population: ITT analysis set - All analyzable participants who received placebo on Day 1 of Part A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Standing SBP | 4 Hours Post-dose | -3.8 mmHg | Standard Deviation 8.8 |
| Part A: TD-9855 1 mg | Part A: Change From Time-matched Placebo in Standing SBP | 7 Hours Post-dose | 12.0 mmHg | Standard Deviation 11.92 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Standing SBP | 4 Hours Post-dose | 8.6 mmHg | Standard Deviation 14.13 |
| Part A: TD-9855 2.5 mg | Part A: Change From Time-matched Placebo in Standing SBP | 7 Hours Post-dose | 12.9 mmHg | Standard Deviation 20.4 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Standing SBP | 4 Hours Post-dose | 6.8 mmHg | Standard Deviation 15.85 |
| Part A: TD-9855 5 mg | Part A: Change From Time-matched Placebo in Standing SBP | 7 Hours Post-dose | 8.9 mmHg | Standard Deviation 11.14 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Standing SBP | 7 Hours Post-dose | 3.8 mmHg | Standard Deviation 5.94 |
| Part A: TD-9855 10 mg | Part A: Change From Time-matched Placebo in Standing SBP | 4 Hours Post-dose | 8.5 mmHg | Standard Deviation 9.57 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Standing SBP | 4 Hours Post-dose | 6.2 mmHg | Standard Deviation 3.77 |
| Part A: TD-9855 20 mg | Part A: Change From Time-matched Placebo in Standing SBP | 7 Hours Post-dose | 0.4 mmHg | Standard Deviation 11.67 |
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.
Time frame: Baseline and 7 hours post-dose on Day 1
Population: ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Duration of Standing During the OST | 3.38 minutes | Standard Deviation 5.275 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Duration of Standing During the OST | 0.15 minutes | Standard Deviation 0.508 |
Comparison: 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.p-value: 0.039995% CI: [-8.57, -0.23]Repeated-measures Mixed-effect Model
Secondary
Part B: Change From Baseline in Seated SBP
Baseline was defined as the pre-dose measurement on Day 1 of Part B.
Time frame: Baseline and 4, 7, 9 and 12 hours post-dose on Day 1
Population: ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Seated SBP | 4 Hours Post-dose | -9.70 mmHg | Standard Deviation 26.397 |
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Seated SBP | 7 Hours Post-dose | 0.30 mmHg | Standard Deviation 27.665 |
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Seated SBP | 9 Hours Post-dose | 6.70 mmHg | Standard Deviation 29.668 |
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Seated SBP | 12 Hours Post-dose | 9.90 mmHg | Standard Deviation 32.809 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Seated SBP | 12 Hours Post-dose | -6.90 mmHg | Standard Deviation 43.118 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Seated SBP | 4 Hours Post-dose | 11.20 mmHg | Standard Deviation 26.407 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Seated SBP | 9 Hours Post-dose | 7.40 mmHg | Standard Deviation 19.415 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Seated SBP | 7 Hours Post-dose | 9.00 mmHg | Standard Deviation 13.139 |
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.
Time frame: Baseline, 4 and 7 hours post-dose on Day 1
Population: ITT analysis set - All analyzable participants who received any amount of placebo or TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Standing SBP | 4 Hours Post-dose | -5.0 mmHg | Standard Deviation 8.49 |
| Part A: TD-9855 1 mg | Part B: Change From Baseline in Standing SBP | 7 Hours Post-dose | -4.0 mmHg | Standard Deviation 12 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Standing SBP | 4 Hours Post-dose | 20.5 mmHg | Standard Deviation 2.12 |
| Part A: TD-9855 2.5 mg | Part B: Change From Baseline in Standing SBP | 7 Hours Post-dose | 21.5 mmHg | Standard Deviation 9.19 |
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.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Duration of Standing During the OST | Day 1 | 0.942 minutes | Standard Deviation 4.2861 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Duration of Standing During the OST | Day 29 | 1.328 minutes | Standard Deviation 3.4217 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Duration of Standing During the OST | Day 85 | 4.069 minutes | Standard Deviation 6.6833 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Duration of Standing During the OST | Day 140 | 4.380 minutes | Standard Deviation 6.1494 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Duration of Standing During the OST | Day 155 | 4.533 minutes | Standard Deviation 7.3741 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Duration of Standing During the OST | Day 169 | 1.923 minutes | Standard Deviation 7.3697 |
Secondary
Part C: Change From Baseline in Seated SBP
Baseline was defined as the pre-breakfast measurement on Day 1.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Seated SBP | Day 1 | 11.19 mmHg | Standard Deviation 23.792 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Seated SBP | Day 29 | 7.56 mmHg | Standard Deviation 26.487 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Seated SBP | Day 85 | 7.81 mmHg | Standard Deviation 25.109 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Seated SBP | Day 140 | 13.36 mmHg | Standard Deviation 33.787 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Seated SBP | Day 155 | 15.23 mmHg | Standard Deviation 23.648 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Seated SBP | Day 169 | 12.10 mmHg | Standard Deviation 35.624 |
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.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Standing SBP | Day 1 | 15.5 mmHg | Standard Deviation 14.711 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Standing SBP | Day 29 | 7.6 mmHg | Standard Deviation 22.37 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Standing SBP | Day 85 | 23.0 mmHg | Standard Deviation 19.21 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Standing SBP | Day 140 | 21.0 mmHg | Standard Deviation 44.03 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Standing SBP | Day 155 | 23.2 mmHg | Standard Deviation 43.64 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Standing SBP | Day 169 | 47.2 mmHg | Standard Deviation 52.18 |
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.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 1 Pre-lunch | 5.60 mmHg | Standard Deviation 13.245 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 2 Pre-breakfast | -2.60 mmHg | Standard Deviation 20.689 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 2 Pre-lunch | 2.76 mmHg | Standard Deviation 12.802 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 15 Pre-breakfast | 5.09 mmHg | Standard Deviation 17.448 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 15 Pre-lunch | 10.03 mmHg | Standard Deviation 14.842 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 29 Pre-breakfast | 9.38 mmHg | Standard Deviation 17.736 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 29 Pre-lunch | 3.53 mmHg | Standard Deviation 15.174 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 85 Pre-breakfast | 2.19 mmHg | Standard Deviation 15.788 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 85 Pre-lunch | 4.38 mmHg | Standard Deviation 21.349 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 140 Pre-breakfast | 0.73 mmHg | Standard Deviation 19.159 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 140 Pre-lunch | 1.82 mmHg | Standard Deviation 18 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 155 Pre-breakfast | 2.68 mmHg | Standard Deviation 23.703 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 155 Pre-lunch | 1.36 mmHg | Standard Deviation 19.694 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 169 Pre-breakfast | 1.50 mmHg | Standard Deviation 14.65 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in Supine SBP to Seated SBP | Day 169 Pre-lunch | 2.95 mmHg | Standard Deviation 18.669 |
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.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 29 | -0.97 score on a scale | Standard Deviation 2.78 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 57 | -0.78 score on a scale | Standard Deviation 2.726 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 85 | -0.45 score on a scale | Standard Deviation 2.276 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 113 | -1.33 score on a scale | Standard Deviation 2.556 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 140 | -1.36 score on a scale | Standard Deviation 2.537 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 155 | -0.21 score on a scale | Standard Deviation 3.203 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Composite OHSA Score | Day 169 | 0.55 score on a scale | Standard Deviation 2.467 |
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.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 155 | -0.86 score on a scale | Standard Deviation 3.328 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 29 | -1.12 score on a scale | Standard Deviation 2.889 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 57 | -1.49 score on a scale | Standard Deviation 2.438 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 85 | -2.11 score on a scale | Standard Deviation 2.398 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 113 | -1.63 score on a scale | Standard Deviation 2.424 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 140 | -1.83 score on a scale | Standard Deviation 2.61 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | Day 169 | -0.69 score on a scale | Standard Deviation 2.509 |
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.
Time frame: Baseline to Day 169
Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 29 | -1.04 score on a scale | Standard Deviation 2.531 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 57 | -1.14 score on a scale | Standard Deviation 2.29 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 85 | -1.28 score on a scale | Standard Deviation 1.966 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 113 | -1.48 score on a scale | Standard Deviation 2.253 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 140 | -1.60 score on a scale | Standard Deviation 2.273 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 155 | -0.53 score on a scale | Standard Deviation 3.0711 |
| Part A: TD-9855 1 mg | Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | Day 169 | -0.07 score on a scale | Standard Deviation 2.276 |