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

Phase 2

Completed

Conditions: Multiple System Atrophy (MSA) With Orthostatic Hypotension
Pure Autonomic Failure
Parkinson Disease With Orthostatic Hypotension
Hypotension, Orthostatic
Parkinson Disease
Orthostatic Hypotension
Neurogenic Orthostatic Hypotension
Pure Autonomic Failure With Orthostatic Hypotension

Interventions: Drug: TD-9855
Drug: Placebo

Registration Number: NCT02705755

Lead Sponsor: Theravance Biopharma

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 34

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TD-9855 Part A	Placebo	Subjects will receive placebo and escalating single doses of TD-9855
TD-9855 Part C	Placebo	Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.
TD-9855 Part B	Placebo	Subjects will receive a single dose of TD-9855 or placebo.
TD-9855 Part A	TD-9855	Subjects will receive placebo and escalating single doses of TD-9855
TD-9855 Part C	TD-9855	Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.
TD-9855 Part B	TD-9855	Subjects will receive a single dose of TD-9855 or placebo.

Primary Outcome Measures

Name	Time	Method
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.
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).

Secondary Outcome Measures

Name	Time	Method
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 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 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 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 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 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.
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 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 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 Seated SBP	Baseline to Day 169	Baseline was defined as the pre-breakfast measurement on Day 1.
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 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 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 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 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.