Clinical trial NCT02705755: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: Theravance Biopharma
Sponsor class: INDUSTRY
First posted: 2016-03-10
Enrollment: 34
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Part A: Change From Time-matched Placebo in Seated Systolic Blood Pressure (SBP)
timeFrame: 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
measure: Part B: Change From Baseline in Seated SBP
timeFrame: Baseline and 7 hours post-dose on Day 1
measure: Part C: Change From Baseline in Likert Scale Score at Week 4
timeFrame: Baseline to Week 4
Secondary outcomes:
measure: Part A and Part B: Change From Baseline in Likert Scale Score at 6 to 8 Hours
timeFrame: Baseline to a single time point between 6 to 8 hours post-dose
measure: Part A and Part B: Change From Baseline in the Composite Orthostatic Hypotension Symptom Assessment (OHSA) Score
timeFrame: Baseline to a single time point between 6 to 8 hours post-dose
measure: Part A: Change From Time-matched Placebo in Standing SBP
timeFrame: 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
measure: Part B: Change From Baseline in Standing SBP
timeFrame: Baseline, 4 and 7 hours post-dose on Day 1
measure: Part A: Change From Time-matched Placebo in Seated SBP
timeFrame: 4, 7, 9, 12 hours post-dose on Day 1 (placebo) and Days 2 to 5 (TD-9855 dosing)
measure: Part B: Change From Baseline in Seated SBP
timeFrame: Baseline and 4, 7, 9 and 12 hours post-dose on Day 1
measure: Part A: Change From Time-matched Placebo in Duration of Standing During the Orthostatic Standing Test (OST)
timeFrame: 4 and 7 hours post-dose on Day 1 (Placebo dosing) and on each of Days 2 to 5 (TD-9855 dosing)
measure: Part B: Change From Baseline in Duration of Standing During the OST
timeFrame: Baseline and 7 hours post-dose on Day 1
measure: Part C: Change From Baseline in the Composite OHSA Score
timeFrame: Baseline to Day 169
measure: Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS)
timeFrame: Baseline to Day 169
measure: Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score
timeFrame: Baseline to Day 169
measure: Part C: Change From Baseline in Standing SBP
timeFrame: Baseline to Day 169
measure: Part C: Change From Baseline in Seated SBP
timeFrame: Baseline to Day 169
measure: Part C: Change From Baseline in Duration of Standing During the OST
timeFrame: Baseline to Day 169
measure: Part C: Change From Baseline in Supine SBP to Seated SBP
timeFrame: Baseline to Day 169
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Theravance Biopharma Investigational Site
state: California
city: Farmington Hills
country: United States
facility: Theravance Biopharma Investigational Site
state: Michigan
city: Berlin
country: United States
facility: Theravance Biopharma Investigational Site
state: New Jersey
city: New York
country: United States
facility: Theravance Biopharma Investigational Site
state: New York
city: Nashville
country: United States
facility: Theravance Biopharma Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: Theravance Biopharma Investigational Site
state: Texas
Study officials:
affiliation: Theravance Biopharma, US, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
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.
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.