Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 48
- 试验地点
- 2
- 主要终点
- Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score
研究概览
简要总结
Drug therapy for patients suffering from autonomic failure and neurogenic orthostatic hypotension are scarce and not effective. If left untreated, these patients have the highest risk of syncope, falls and fall-related injuries. The proposed study will determine the clinical benefit of a commercially available drug, atomoxetine, to reduce symptoms associated with neurogenic orthostatic hypotension in patients with autonomic failure.
详细描述
Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. These patients develop neurogenic orthostatic hypotension (OH) because of impaired autonomic reflexes that control cardiovascular and neuro-humoral adaptation to upright posture. The treatment of neurogenic OH is challenging; the therapeutic options are scarce, and some patients are refractory to treatment.
Atomoxetine is a selective norepinephrine transporter inhibitor that increases the availability of norepinephrine in the synapse by blocking its reuptake. Our preliminary data in sixty-five patients with primary autonomic failure and neurogenic OH showed that atomoxetine was more effective than midodrine, standard of care, in improving standing SBP (+7.5 mm Hg). Notably, only atomoxetine and not midodrine induced a significant reduction in OH-related symptoms (lightheadedness and dizziness) compared with placebo. In this proposal, we will test the hypothesis that prolonged administration of the norepinephrine transporter blocker, atomoxetine, improves OH-related symptoms and OH-impact on daily activities compared with placebo in autonomic failure patients. We propose a randomized, double-blind, placebo-controlled, 2x2 crossover study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •40 years old or older
- •Neurogenic Orthostatic Hypotension (defined by a reduction of ≥20 mmHg drop in SBP within 3 minutes of standing, associated with impaired autonomic reflexes as assessed by autonomic function tests.
排除标准
- •Pregnancy or breastfeeding
- •Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria, anaphylaxis)
- •Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion), Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella (milnacipran)
- •Previous history (within 14 days prior to enrollment) and current use of monoamine oxidase inhibitors
- •Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine, fluoxetine, quinidine
- •Pre-existing sustained severe hypertension (BP ≥ 140/80 mmhg in the sitting position)
- •Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >2 x upper limit of normal range)
- •Impaired renal function (serum creatinine equal or more than 1.6 mg/dl)
- •Myocardial infarction within 6 months prior to enrollment
- •Congestive heart failure (LV hypertrophy acceptable)
- •History of serious neurologic disease such as cerebral hemorrhage, or stroke
- •Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, unlikelihood of completing the study, and mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
- •Narrow-angle glaucoma
研究组 & 干预措施
placebo
placebo capsules
干预措施: Atomoxetine (Drug)
atomoxetine
atomoxetine capsules 10 mg or 18 mg
干预措施: Placebo (Drug)
结局指标
主要结局
Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score
时间窗: week 0 to week 4
The Orthostatic Hypotension Questionnaire (OHQ) , patient-reported assessment tool consisting of the OH Symptom Assessment (OHSA), OH Daily Activity Scale (OHDAS). The composite score is composed of 10 individual items: 6 items measure specific symptoms , the Orthostatic Hypotension Symptom Assessment (OHSA), and 4 items measure the impact of those symptoms on a patient daily activities, the Orthostatic Hypotension Daily Activity Scale (OHDAS). This scales helps to measure the impact of orthostatic symptoms on daily. Scale is between 0-10: where "0" is minimum Orthostatic symptoms and "10" is the maximum / worse possible severity of the symptoms. All items are scored 0 through 10 (higher scores = more impact) and summed into the respective total scores. The OHSA and OHDAS subscales averaged to compute the OHQ composite score.
次要结局
- Change in Blood Pressure(Baseline to 4 weeks)
- Change in Heart Rate (HR)(Baseline and at 4 weeks)
研究者
Cyndya Shibao, MD
Associate Professor of Medicine
Vanderbilt University Medical Center