TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH)

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

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

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)

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

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)

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

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)

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

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

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

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

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

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

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

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