Trial Outcomes & Findings for TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH) (NCT NCT02705755)

Last Updated: 2022-09-26

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

34 participants

Primary outcome timeframe

7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)

Results posted on

2022-09-26

Participant Flow

34 participants were enrolled across 6 sites in the United States between September 2017 and November 2018.

34 participants were screened and all were enrolled and treated with study drug.

Participant milestones

Participant milestones
Measure	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.	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.	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.	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.
Part A (6 Days) STARTED	34	0	0	0
Part A (6 Days) Participants Who Received Placebo	34	0	0	0
Part A (6 Days) Participants Who Received 1 mg Study Drug	17	0	0	0
Part A (6 Days) Participants Who Received 2.5 mg Study Drug	31	0	0	0
Part A (6 Days) Participants Who Received 5 mg Study Drug	29	0	0	0
Part A (6 Days) Participants Who Received 10 mg Study Drug	28	0	0	0
Part A (6 Days) Participants Who Received 20 mg Study Drug	13	0	0	0
Part A (6 Days) Participants Who Rolled to Part B	10	0	0	0
Part A (6 Days) Participants Who Rolled to Part C	21	0	0	0
Part A (6 Days) COMPLETED	29	0	0	0
Part A (6 Days) NOT COMPLETED	5	0	0	0
Part B (1 Day) STARTED	0	5	5	0
Part B (1 Day) Received Study Drug	0	5	5	0
Part B (1 Day) COMPLETED	0	5	5	0
Part B (1 Day) NOT COMPLETED	0	0	0	0
Part C (20 Weeks) STARTED	0	0	0	21
Part C (20 Weeks) Received Study Drug	0	0	0	21
Part C (20 Weeks) COMPLETED	0	0	0	11
Part C (20 Weeks) NOT COMPLETED	0	0	0	10

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Part A (6 Days) Adverse Event	1	0
Part A (6 Days) Physician Decision	3	0
Part A (6 Days) Withdrawal by Subject	1	0
Part C (20 Weeks) Physician Decision	0	2
Part C (20 Weeks) Adverse Event	0	6
Part C (20 Weeks) Withdrawal by Subject	0	2

Baseline Characteristics

The number analyzed in each row is based on the number of participants enrolled in that part of the study.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Study Participants n=34 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.
Age, Continuous Part A: Dose Escalation (Within Group)	65.8 years STANDARD_DEVIATION 7.94 • n=34 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Age, Continuous Part B: Randomized - Placebo	65.2 years STANDARD_DEVIATION 8.98 • n=5 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Age, Continuous Part B: Randomized - TD-9855	66.4 years STANDARD_DEVIATION 5.22 • n=5 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Age, Continuous Part C: Dose Extension	64.1 years STANDARD_DEVIATION 7.91 • n=21 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part A: Part A: Dose Escalation (Within Group) · Female	12 Participants n=34 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part A: Part A: Dose Escalation (Within Group) · Male	22 Participants n=34 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part B: Randomized - Placebo · Female	2 Participants n=5 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part B: Randomized - Placebo · Male	3 Participants n=5 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part B: Randomized - TD-9855 · Female	2 Participants n=5 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part B: Randomized - TD-9855 · Male	3 Participants n=5 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part C: Dose Extension · Female	9 Participants n=21 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Sex: Female, Male Part C: Dose Extension · Male	12 Participants n=21 Participants • The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part A: Dose Escalation (Within Group) · Hispanic or Latino	3 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part A: Dose Escalation (Within Group) · Not Hispanic or Latino	30 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part A: Dose Escalation (Within Group) · Unknown or Not Reported	1 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part B: Randomized - Placebo · Hispanic or Latino	1 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part B: Randomized - Placebo · Not Hispanic or Latino	4 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part B: Randomized - Placebo · Unknown or Not Reported	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part B: Randomized - TD-9855 · Hispanic or Latino	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part B: Randomized - TD-9855 · Not Hispanic or Latino	5 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part B: Randomized - TD-9855 · Unknown or Not Reported	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part C: Dose Extension · Hispanic or Latino	2 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part C: Dose Extension · Not Hispanic or Latino	18 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Ethnicity (NIH/OMB) Part C: Dose Extension · Unknown or Not Reported	1 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · American Indian or Alaska Native	0 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · Asian	1 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · Native Hawaiian or Other Pacific Islander	0 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · Black or African American	2 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · White	31 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · More than one race	0 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part A: Dose Escalation (Within Group) · Unknown or Not Reported	0 Participants n=34 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · American Indian or Alaska Native	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · Asian	1 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · Black or African American	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · White	4 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · More than one race	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - Placebo · Unknown or Not Reported	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · American Indian or Alaska Native	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · Asian	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · Black or African American	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · White	5 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · More than one race	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part B: Randomized - TD-9855 · Unknown or Not Reported	0 Participants n=5 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · American Indian or Alaska Native	0 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · Asian	1 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · Native Hawaiian or Other Pacific Islander	0 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · Black or African American	2 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · White	18 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · More than one race	0 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.
Race (NIH/OMB) Part C: Dose Extension · Unknown or Not Reported	0 Participants n=21 Participants • Measure Analysis Population Description: The number analyzed in each row is based on the number of participants enrolled in that part of the study.

PRIMARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=17 Participants 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.	Part A: TD-9855 2.5 mg n=30 Participants 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).	Part A: TD-9855 5 mg n=28 Participants 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).	Part A: TD-9855 10 mg n=28 Participants 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).	Part A: TD-9855 20 mg n=13 Participants 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.	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.	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.	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.
Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP)	0.2 millimeter of mercury (mmHg) Standard Deviation 18.58	-1.8 millimeter of mercury (mmHg) Standard Deviation 20.27	-3.4 millimeter of mercury (mmHg) Standard Deviation 16.50	-2.9 millimeter of mercury (mmHg) Standard Deviation 21.53	-7.3 millimeter of mercury (mmHg) Standard Deviation 18.86	—	—	—

PRIMARY outcome

Timeframe: 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.

Baseline was defined as the pre-dose measurement on Day 1 of Part B.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=5 Participants 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.	Part A: TD-9855 2.5 mg n=5 Participants 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).	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).	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).	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.	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.	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.	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.
Part B: Change From Baseline in Seated SBP	0.30 mmHg Standard Deviation 27.655	9.00 mmHg Standard Deviation 13.139	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Baseline to Week 4

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=16 Participants 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.	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).	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).	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).	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.	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.	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.	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.
Part C: Change From Baseline in Likert Scale Score at Week 4	-2.4 score on a scale Standard Deviation 4.54	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=33 Participants 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.	Part A: TD-9855 2.5 mg n=16 Participants 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).	Part A: TD-9855 5 mg n=29 Participants 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).	Part A: TD-9855 10 mg n=27 Participants 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).	Part A: TD-9855 20 mg n=27 Participants 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.	Part A: TD-9855 20 mg n=13 Participants 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.	Part B: Randomized - Placebo n=5 Participants 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.	Part B: Randomized - TD-9855 n=5 Participants 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.
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	-0.9 score on a scale Standard Deviation 4.08	-1.4 score on a scale Standard Deviation 3.61	-1.3 score on a scale Standard Deviation 3.59	-2.0 score on a scale Standard Deviation 3.66	-2.2 score on a scale Standard Deviation 3.19	-1.6 score on a scale Standard Deviation 3.44	-1.8 score on a scale Standard Deviation 2.28

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=33 Participants 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.	Part A: TD-9855 2.5 mg n=16 Participants 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).	Part A: TD-9855 5 mg n=29 Participants 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).	Part A: TD-9855 10 mg n=27 Participants 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).	Part A: TD-9855 20 mg n=27 Participants 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.	Part A: TD-9855 20 mg n=13 Participants 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.	Part B: Randomized - Placebo n=5 Participants 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.	Part B: Randomized - TD-9855 n=5 Participants 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.
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	-0.30 score on a scale Standard Deviation 2.157	-0.64 score on a scale Standard Deviation 1.730	-0.78 score on a scale Standard Deviation 2.232	-1.22 score on a scale Standard Deviation 2.625	-1.31 score on a scale Standard Deviation 2.340	-1.0 score on a scale Standard Deviation 2.64	-0.3 score on a scale Standard Deviation 1.74

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=7 Participants 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.	Part A: TD-9855 2.5 mg n=13 Participants 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).	Part A: TD-9855 5 mg n=12 Participants 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).	Part A: TD-9855 10 mg n=11 Participants 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).	Part A: TD-9855 20 mg n=5 Participants 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.	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.	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.	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.
Part A: Change From Time-matched Placebo in Standing SBP 4 Hours Post-dose	-3.8 mmHg Standard Deviation 8.80	8.6 mmHg Standard Deviation 14.13	6.8 mmHg Standard Deviation 15.85	8.5 mmHg Standard Deviation 9.57	6.2 mmHg Standard Deviation 3.77	—	—	—
Part A: Change From Time-matched Placebo in Standing SBP 7 Hours Post-dose	12.0 mmHg Standard Deviation 11.92	12.9 mmHg Standard Deviation 20.40	8.9 mmHg Standard Deviation 11.14	3.8 mmHg Standard Deviation 5.94	0.4 mmHg Standard Deviation 11.67	—	—	—

SECONDARY outcome

Timeframe: 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.

SBP was measured after 3 minutes of standing. Baseline was defined as the pre-dose measurement on Day 1 of Part B.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=3 Participants 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.	Part A: TD-9855 2.5 mg n=2 Participants 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).	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).	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).	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.	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.	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.	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.
Part B: Change From Baseline in Standing SBP 4 Hours Post-dose	-5.0 mmHg Standard Deviation 8.49	20.5 mmHg Standard Deviation 2.12	—	—	—	—	—	—
Part B: Change From Baseline in Standing SBP 7 Hours Post-dose	-4.0 mmHg Standard Deviation 12.00	21.5 mmHg Standard Deviation 9.19	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=17 Participants 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.	Part A: TD-9855 2.5 mg n=31 Participants 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).	Part A: TD-9855 5 mg n=28 Participants 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).	Part A: TD-9855 10 mg n=28 Participants 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).	Part A: TD-9855 20 mg n=13 Participants 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.	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.	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.	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.
Part A: Change From Time-matched Placebo in Seated SBP 4 Hours Post-dose	-3.2 mmHg Standard Deviation 15.89	2.4 mmHg Standard Deviation 15.24	5.9 mmHg Standard Deviation 21.85	4.9 mmHg Standard Deviation 20.14	0.7 mmHg Standard Deviation 17.40	—	—	—
Part A: Change From Time-matched Placebo in Seated SBP 7 Hours Post-dose	0.2 mmHg Standard Deviation 18.58	-1.8 mmHg Standard Deviation 20.27	-3.4 mmHg Standard Deviation 16.50	-2.9 mmHg Standard Deviation 21.53	-7.3 mmHg Standard Deviation 18.86	—	—	—
Part A: Change From Time-matched Placebo in Seated SBP 9 Hours Post-dose	4.1 mmHg Standard Deviation 19.08	0.7 mmHg Standard Deviation 18.90	5.5 mmHg Standard Deviation 21.14	2.5 mmHg Standard Deviation 20.85	9.8 mmHg Standard Deviation 26.48	—	—	—
Part A: Change From Time-matched Placebo in Seated SBP 12 Hours Post-dose	2.4 mmHg Standard Deviation 22.20	-1.4 mmHg Standard Deviation 17.44	0.4 mmHg Standard Deviation 19.86	7.4 mmHg Standard Deviation 24.88	-2.5 mmHg Standard Deviation 14.42	—	—	—

SECONDARY outcome

Timeframe: 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.

Baseline was defined as the pre-dose measurement on Day 1 of Part B.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=5 Participants 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.	Part A: TD-9855 2.5 mg n=5 Participants 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).	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).	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).	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.	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.	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.	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.
Part B: Change From Baseline in Seated SBP 9 Hours Post-dose	6.70 mmHg Standard Deviation 29.668	7.40 mmHg Standard Deviation 19.415	—	—	—	—	—	—
Part B: Change From Baseline in Seated SBP 12 Hours Post-dose	9.90 mmHg Standard Deviation 32.809	-6.90 mmHg Standard Deviation 43.118	—	—	—	—	—	—
Part B: Change From Baseline in Seated SBP 4 Hours Post-dose	-9.70 mmHg Standard Deviation 26.397	11.20 mmHg Standard Deviation 26.407	—	—	—	—	—	—
Part B: Change From Baseline in Seated SBP 7 Hours Post-dose	0.30 mmHg Standard Deviation 27.665	9.00 mmHg Standard Deviation 13.139	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=17 Participants 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.	Part A: TD-9855 2.5 mg n=31 Participants 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).	Part A: TD-9855 5 mg n=28 Participants 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).	Part A: TD-9855 10 mg n=28 Participants 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).	Part A: TD-9855 20 mg n=13 Participants 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.	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.	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.	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.
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	0.799 minutes Standard Deviation 2.7898	1.085 minutes Standard Deviation 3.4188	1.579 minutes Standard Deviation 3.5527	1.081 minutes Standard Deviation 2.8553	—	—	—
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	1.343 minutes Standard Deviation 2.7847	0.952 minutes Standard Deviation 3.6232	0.986 minutes Standard Deviation 4.3645	1.159 minutes Standard Deviation 2.8264	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=5 Participants 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.	Part A: TD-9855 2.5 mg n=5 Participants 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).	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).	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).	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.	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.	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.	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.
Part B: Change From Baseline in Duration of Standing During the OST	3.38 minutes Standard Deviation 5.275	0.15 minutes Standard Deviation 0.5080	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=16 Participants 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.	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).	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).	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).	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.	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.	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.	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.
Part C: Change From Baseline in the Composite OHSA Score Day 57	-0.78 score on a scale Standard Deviation 2.726	—	—	—	—	—	—	—
Part C: Change From Baseline in the Composite OHSA Score Day 29	-0.97 score on a scale Standard Deviation 2.780	—	—	—	—	—	—	—
Part C: Change From Baseline in the Composite OHSA Score Day 85	-0.45 score on a scale Standard Deviation 2.276	—	—	—	—	—	—	—
Part C: Change From Baseline in the Composite OHSA Score Day 113	-1.33 score on a scale Standard Deviation 2.556	—	—	—	—	—	—	—
Part C: Change From Baseline in the Composite OHSA Score Day 140	-1.36 score on a scale Standard Deviation 2.537	—	—	—	—	—	—	—
Part C: Change From Baseline in the Composite OHSA Score Day 155	-0.21 score on a scale Standard Deviation 3.203	—	—	—	—	—	—	—
Part C: Change From Baseline in the Composite OHSA Score Day 169	0.55 score on a scale Standard Deviation 2.467	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=16 Participants 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.	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).	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).	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).	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.	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.	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.	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.
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 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 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 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 C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) Day 140	-1.83 score on a scale Standard Deviation 2.610	—	—	—	—	—	—	—
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 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 outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

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.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=16 Participants 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.	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).	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).	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).	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.	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.	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.	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.
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 C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score Day 29	-1.04 score on a scale Standard Deviation 2.531	—	—	—	—	—	—	—
Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score Day 57	-1.14 score on a scale Standard Deviation 2.290	—	—	—	—	—	—	—
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 C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score Day 140	-1.60 score on a scale Standard Deviation 2.273	—	—	—	—	—	—	—
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 C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score Day 169	-0.07 score on a scale Standard Deviation 2.276	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

SBP was measured after 3 minutes of standing. Baseline was defined as the pre-lunch measurement on Day 1.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=11 Participants 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.	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).	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).	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).	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.	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.	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.	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.
Part C: Change From Baseline in Standing SBP Day 29	7.6 mmHg Standard Deviation 22.37	—	—	—	—	—	—	—
Part C: Change From Baseline in Standing SBP Day 85	23.0 mmHg Standard Deviation 19.21	—	—	—	—	—	—	—
Part C: Change From Baseline in Standing SBP Day 140	21.0 mmHg Standard Deviation 44.03	—	—	—	—	—	—	—
Part C: Change From Baseline in Standing SBP Day 155	23.2 mmHg Standard Deviation 43.64	—	—	—	—	—	—	—
Part C: Change From Baseline in Standing SBP Day 1	15.5 mmHg Standard Deviation 14.711	—	—	—	—	—	—	—
Part C: Change From Baseline in Standing SBP Day 169	47.2 mmHg Standard Deviation 52.18	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

Baseline was defined as the pre-breakfast measurement on Day 1.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=21 Participants 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.	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).	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).	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).	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.	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.	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.	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.
Part C: Change From Baseline in Seated SBP Day 1	11.19 mmHg Standard Deviation 23.792	—	—	—	—	—	—	—
Part C: Change From Baseline in Seated SBP Day 29	7.56 mmHg Standard Deviation 26.487	—	—	—	—	—	—	—
Part C: Change From Baseline in Seated SBP Day 85	7.81 mmHg Standard Deviation 25.109	—	—	—	—	—	—	—
Part C: Change From Baseline in Seated SBP Day 140	13.36 mmHg Standard Deviation 33.787	—	—	—	—	—	—	—
Part C: Change From Baseline in Seated SBP Day 155	15.23 mmHg Standard Deviation 23.648	—	—	—	—	—	—	—
Part C: Change From Baseline in Seated SBP Day 169	12.10 mmHg Standard Deviation 35.624	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

Outcome measures

Outcome measures
Measure	Part A: TD-9855 1 mg n=21 Participants 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.	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).	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).	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).	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.	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.	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.	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.
Part C: Change From Baseline in Duration of Standing During the OST Day 169	1.923 minutes Standard Deviation 7.3697	—	—	—	—	—	—	—
Part C: Change From Baseline in Duration of Standing During the OST Day 1	0.942 minutes Standard Deviation 4.2861	—	—	—	—	—	—	—
Part C: Change From Baseline in Duration of Standing During the OST Day 29	1.328 minutes Standard Deviation 3.4217	—	—	—	—	—	—	—
Part C: Change From Baseline in Duration of Standing During the OST Day 85	4.069 minutes Standard Deviation 6.6833	—	—	—	—	—	—	—
Part C: Change From Baseline in Duration of Standing During the OST Day 140	4.380 minutes Standard Deviation 6.1494	—	—	—	—	—	—	—
Part C: Change From Baseline in Duration of Standing During the OST Day 155	4.533 minutes Standard Deviation 7.3741	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: ITT analysis set - All analyzable participants who received at least 1 dose of TD-9855.

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.