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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Study to Assess the Effect of TD-9855 in Subjects With Neurogenic Orthostatic Hypotension

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

Intervention / Treatment
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* Drug: TD-9855
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TD-9855 Part A<br>Subjects will receive placebo and escalating single doses of TD-9855 | Drug: TD-9855<br>* Administered orally.<br>Drug: Placebo<br>* Administered orally.<br>|
| Experimental: TD-9855 Part B<br>Subjects will receive a single dose of TD-9855 or placebo. | Drug: TD-9855<br>* Administered orally.<br>Drug: Placebo<br>* Administered orally.<br>|
| Experimental: TD-9855 Part C<br>Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm. | Drug: TD-9855<br>* Administered orally.<br>Drug: Placebo<br>* Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP) | Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1). | 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing) | 
| Part B: Change From Baseline in Seated SBP | Baseline was defined as the pre-dose measurement on Day 1 of Part B. | Baseline and 7 hours post-dose on Day 1 | 
| Part C: Change From Baseline in Likert Scale Score at Week 4 | The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A higher score indicates a worse outcome. Baseline was defined as the pre-lunch measurement on Day -1. | Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours | The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A higher score indicates a worse outcome. Baseline was defined as the pre-dose measurement on Day 1 for Part A and Part B. Data was collected a one point between 6 and 8 hours post-dose. | Baseline to a single time point between 6 to 8 hours post-dose | 
| Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score | The OHSA is made up of a 6-item symptoms assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. A reduction in composite score indicates an improvement in symptoms. Baseline was defined as the pre-dose measurement on Day 1 for Part A and Part B. Data was collected a one point between 6 and 8 hours post-dose. | Baseline to a single time point between 6 to 8 hours post-dose | 
| Part A: Change From Time-matched Placebo in Standing SBP | Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1). SBP was measured after 5 minutes of standing. | 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing) | 
| Part B: Change From Baseline in Standing SBP | SBP was measured after 3 minutes of standing. Baseline was defined as the pre-dose measurement on Day 1 of Part B. | Baseline, 4 and 7 hours post-dose on Day 1 | 
| Part A: Change From Time-matched Placebo in Seated SBP | Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1). | 4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing) | 
| Part B: Change From Baseline in Seated SBP | Baseline was defined as the pre-dose measurement on Day 1 of Part B. | Baseline and 4, 7, 9 and 12 hours post-dose on Day 1 | 
| Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST) | Blood pressure (BP) and heart rate (HR) measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1) of Part A. | 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing) | 
| Part B: Change From Baseline in Duration of Standing During the OST | BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Baseline was defined as the predose measurement on Day 1 of Part B. | Baseline and 7 hours post-dose on Day 1 | 
| Part C: Change From Baseline in the Composite OHSA Score | The OHSA is made up of a 6-item symptoms assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting cannot be done for other reasons. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. Baseline was defined as the pre-lunch measurement on Day -1. | Baseline to Day 169 | 
| Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS) | The OHDAS is made up of a 4-item daily activity assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting cannot be done for other reasons. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHDAS score is the average of the response scores (for non-missing data) to the 4 questions of OHDAS. Baseline was defined as the pre-lunch measurement on Day -1. | Baseline to Day 169 | 
| Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score | The OHQ is a 2-component questionnaire made up of 6-item symptoms assessment referred to as OHSA, and a 4-item daily activity assessment referred to as the OHDAS. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting cannot be done for other reasons. Activities that were marked as zero or cannot be done for other reasons at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. The composite OHDAS score is the average of the response scores (for non-missing data) to the 4 questions of OHDAS. The OHQ composite score is the average of the OHSA and OHDAS composite scores. Baseline was defined as the pre-lunch measurement on Day -1. | Baseline to Day 169 | 
| Part C: Change From Baseline in Standing SBP | SBP was measured after 3 minutes of standing. Baseline was defined as the pre-lunch measurement on Day 1. | Baseline to Day 169 | 
| Part C: Change From Baseline in Seated SBP | Baseline was defined as the pre-breakfast measurement on Day 1. | Baseline to Day 169 | 
| Part C: Change From Baseline in Duration of Standing During the OST | BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Baseline was defined as the pre-breakfast measurement on Day 1. | Baseline to Day 169 | 
| Part C: Change From Baseline in Supine SBP to Seated SBP | Baseline is defined as pre-breakfast measurement on Day 1. The difference in SBP from a supine to a seated position was measured at baseline and at each time point. The change from baseline was calculated at each time point. | Baseline to Day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nOH, MSA, PD, PAF, Orthostatic Hypotension, ampreloxetine, TD-9855, Neurogenic Orthostatic Hypotension (nOH), Multiple System Atrophy (MSA), Pure Autonomic Failure, Parkinson Disease(PD)