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

Primary Purpose

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

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

TD-9855

Placebo

About this trial

This is an interventional treatment trial for Neurogenic Orthostatic Hypotension focused on measuring Neurogenic Orthostatic Hypotension (nOH), Multiple System Atrophy (MSA), Pure Autonomic Failure, Parkinson Disease(PD), nOH, MSA, PD, PAF, Orthostatic Hypotension, ampreloxetine, TD-9855

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Theravance Biopharma Investigational Site
Theravance Biopharma Investigational Site
Theravance Biopharma Investigational Site
Theravance Biopharma Investigational Site
Theravance Biopharma Investigational Site
Theravance Biopharma Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

TD-9855 Part A

TD-9855 Part B

TD-9855 Part C

Arm Description

Subjects will receive placebo and escalating single doses of TD-9855

Subjects will receive a single dose of TD-9855 or 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.

Outcomes

Primary Outcome Measures

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).

Part B: Change From Baseline in Seated SBP

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

The Likert Scale is question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). The question asks participants to rate the severity of their orthostatic hypotension symptoms (dizziness, lightheadedness, feeling faint, or feeling like you might black out) on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A higher score indicates a worse outcome. Baseline was defined as the pre-lunch measurement on Day -1.

Secondary Outcome Measures

Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours

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.

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.

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.

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).

Part B: Change From Baseline in Seated SBP

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

Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST)

Blood pressure (BP) and heart rate (HR) measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1) of Part A.

Part B: Change From Baseline in Duration of Standing During the OST

BP and heart rate HR measurements were recorded with automated (or manual) sphygmomanometer, after being seated for 5 min and 10 min, and after standing for 1, 3, 5, and 10 min. The standing time was measured with a chronometer and the duration of standing was recorded. The total duration of standing may have occurred between 2 of the predefined time points, or the participant may have been able to stand for longer than the 10-min standing test. In either case, the total duration was recorded. Baseline was defined as the predose measurement on Day 1 of Part B.

Part C: Change From Baseline in the Composite OHSA Score

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)

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 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.

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.

Part C: Change From Baseline in Seated SBP

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

Part C: Change From Baseline in Duration of Standing During the OST

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.

Full Information

NCT ID

NCT02705755

First Posted

March 7, 2016

Last Updated

August 30, 2022

Sponsor

Theravance Biopharma

1. Study Identification

Unique Protocol Identification Number

NCT02705755

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Completed

Study Start Date

September 9, 2017 (Actual)

Primary Completion Date

July 24, 2018 (Actual)

Study Completion Date

November 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Theravance Biopharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Neurogenic Orthostatic Hypotension (nOH), Multiple System Atrophy (MSA), Pure Autonomic Failure, Parkinson Disease(PD), nOH, MSA, PD, PAF, Orthostatic Hypotension, ampreloxetine, TD-9855

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TD-9855 Part A

Arm Type

Experimental

Arm Description

Subjects will receive placebo and escalating single doses of TD-9855

Arm Title

TD-9855 Part B

Arm Type

Experimental

Arm Description

Subjects will receive a single dose of TD-9855 or placebo.

Arm Title

TD-9855 Part C

Arm Type

Experimental

Arm Description

Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.

Intervention Type

Drug

Intervention Name(s)

TD-9855

Intervention Description

Administered orally.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Administered orally.

Primary Outcome Measure Information:

Title

Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP)

Description

Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1).

Time Frame

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

Title

Part B: Change From Baseline in Seated SBP

Description

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

Time Frame

Baseline and 7 hours post-dose on Day 1

Title

Part C: Change From Baseline in Likert Scale Score at Week 4

Description

Time Frame

Baseline to Week 4

Secondary Outcome Measure Information:

Title

Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours

Description

Time Frame

Baseline to a single time point between 6 to 8 hours post-dose

Title

Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score

Description

Time Frame

Baseline to a single time point between 6 to 8 hours post-dose

Title

Part A: Change From Time-matched Placebo in Standing SBP

Description

Time Frame

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

Title

Part B: Change From Baseline in Standing SBP

Description

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

Time Frame

Baseline, 4 and 7 hours post-dose on Day 1

Title

Part A: Change From Time-matched Placebo in Seated SBP

Description

Placebo referred to the Day 1 visit, and the change from placebo referred to the time-matched difference from each TD-9855 dosing day (Days 2 through 5) relative to placebo dosing (Day 1).

Time Frame

4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing)

Title

Part B: Change From Baseline in Seated SBP

Description

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

Time Frame

Baseline and 4, 7, 9 and 12 hours post-dose on Day 1

Title

Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST)

Description

Time Frame

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

Title

Part B: Change From Baseline in Duration of Standing During the OST

Description

Time Frame

Baseline and 7 hours post-dose on Day 1

Title

Part C: Change From Baseline in the Composite OHSA Score

Description

The OHSA is made up of a 6-item symptoms assessment. All items were scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference, and the option of selecting "cannot be done for other reasons." Activities that were marked as zero or "cannot be done for other reasons" at baseline were not included in the scoring. The composite OHSA score is the average of the response scores (for non-missing data) to the 6 questions of OHSA. Baseline was defined as the pre-lunch measurement on Day -1.

Time Frame

Baseline to Day 169

Title

Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS)

Description

Time Frame

Baseline to Day 169

Title

Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score

Description

Time Frame

Baseline to Day 169

Title

Part C: Change From Baseline in Standing SBP

Description

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

Time Frame

Baseline to Day 169

Title

Part C: Change From Baseline in Seated SBP

Description

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

Time Frame

Baseline to Day 169

Title

Part C: Change From Baseline in Duration of Standing During the OST

Description

Time Frame

Baseline to Day 169

Title

Part C: Change From Baseline in Supine SBP to Seated SBP

Description

Time Frame

Baseline to Day 169

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Monitor

Organizational Affiliation

Theravance Biopharma, US, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Theravance Biopharma Investigational Site

City

Long Beach

State/Province

California

ZIP/Postal Code

90806

Country

United States

Facility Name

Theravance Biopharma Investigational Site

City

Farmington Hills

State/Province

Michigan

ZIP/Postal Code

48334

Country

United States

Facility Name

Theravance Biopharma Investigational Site

City

Berlin

State/Province

New Jersey

ZIP/Postal Code

08009

Country

United States

Facility Name

Theravance Biopharma Investigational Site

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

Facility Name

Theravance Biopharma Investigational Site

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Theravance Biopharma Investigational Site

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34657222

Citation

Kaufmann H, Vickery R, Wang W, Kanodia J, Shibao CA, Norcliffe-Kaufmann L, Haumann B, Biaggioni I. Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial. Clin Auton Res. 2021 Dec;31(6):699-711. doi: 10.1007/s10286-021-00827-0. Epub 2021 Oct 17.

Results Reference

derived

PubMed Identifier

33782836

Citation

Lo A, Norcliffe-Kaufmann L, Vickery R, Bourdet D, Kanodia J. Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension. Clin Auton Res. 2021 Jun;31(3):395-403. doi: 10.1007/s10286-021-00800-x. Epub 2021 Mar 29.

Results Reference

derived

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

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