A Phase 2 Study to Assess the Effect of TD-9855 in Subjects With Neurogenic Orthostatic Hypotension
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Part B: Change From Baseline in Seated SBP
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
TD-9855 Part A
Subjects will receive placebo and escalating single doses of TD-9855
干预措施: TD-9855 (Drug)
TD-9855 Part A
Subjects will receive placebo and escalating single doses of TD-9855
干预措施: Placebo (Drug)
TD-9855 Part B
Subjects will receive a single dose of TD-9855 or placebo.
干预措施: TD-9855 (Drug)
TD-9855 Part B
Subjects will receive a single dose of TD-9855 or placebo.
干预措施: Placebo (Drug)
TD-9855 Part C
Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.
干预措施: TD-9855 (Drug)
TD-9855 Part C
Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.
干预措施: Placebo (Drug)
结局指标
主要结局
Part B: Change From Baseline in Seated SBP
时间窗: 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
时间窗: 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)
时间窗: 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).
次要结局
- 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)
- Part B: Change From Baseline in Seated SBP(Baseline and 4, 7, 9 and 12 hours post-dose on Day 1)
- Part B: Change From Baseline in Standing SBP(Baseline, 4 and 7 hours post-dose on Day 1)
- Part C: Change From Baseline in the Orthostatic Hypotension Questionnaire (OHQ) Score(Baseline to Day 169)
- Part C: Change From Baseline in Duration of Standing During the OST(Baseline to Day 169)
- 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))
- 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)
- 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))
- Part B: Change From Baseline in Duration of Standing During the OST(Baseline and 7 hours post-dose on Day 1)
- Part C: Change From Baseline in Seated SBP(Baseline to Day 169)
- 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))
- Part C: Change From Baseline in the Composite OHSA Score(Baseline to Day 169)
- Part C: Change From Baseline in the Orthostatic Hypotension Daily Activity Scale (OHDAS)(Baseline to Day 169)
- Part C: Change From Baseline in Supine SBP to Seated SBP(Baseline to Day 169)
- Part C: Change From Baseline in Standing SBP(Baseline to Day 169)