A Double-Blinded, Placebo-Controlled Study To Assess Hemodynamic Changes, Orthostatic Tolerance, Out-Patient Fatigue And Quality Of Life In Neuropathic And Non-Neuropathic POTS Patients In Response To Adrenoreceptor Agonist And Antagonist
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Change Maximal Postural Tachycardia During Tilt
研究概览
简要总结
The purpose of this study is to test the hypothesis that patients with non-neuropathic POTS will have different responsiveness than patients with neuropathic POTS to direct alpha-1 adrenoreceptor agonist therapy (droxidopa) and to non-selective beta-adrenoreceptor antagonist therapy (atenolol).
The specific goal of this protocol is to investigate the effect of atenolol and droxidopa on cardiovascular autonomic functions such as cardiovagal control, sympathetic nerve activity, and sympathetic vascular transduction, systemic hemodynamic response to orthostatic stress and on the quality of life in neuropathic and non-neuropathic patients with postural tachycardia syndrome (POTS).
Standardized tests are used to assess cardiovagal control function, sympathetic nerve activity, sympathetic vascular transduction, systemic hemodynamic response to head-up tilt test and standardized questionnaires to assess the quality of life in patients with POTS.
The cardiovagal, sympathetic and hemodynamic measurements are performed after and during drug administration. To control the effect of medications placebo is used on separate testing visits. The order of drugs and placebo is randomized.
详细描述
The pathophysiological basis of postural tachycardia syndrome (POTS) is not well elucidated. The most widely recognized primary cause of POTS is a "restricted" or "selective" peripheral neuropathy - neuropathic POTS. Several lines of evidence point to a restricted peripheral neuropathy, specifically sympathetic denervation in the lower hemibody, as a cause of POTS. These include venous denervation, impaired distal sudomotor dysfunction, lower norepinephrine spillover in the legs than the arms. However, not all POTS patients have peripheral neuropathy. Proposed pathogenic etiologies for non-neuropathic POTS include deconditioning, low-grade inflammation and oxidative stress. Neuropathic POTS is present in 33% of patients while non-neuropathic POTS is present in 67% of patients.
The most frequent neuropathic feature in the neuropathic POTS group is decreased sweat output measured by quantitative sudomotor axon reflex test. Headache and gastrointestinal symptoms (such as abdominal pain, bloating, nausea and constipation) are also more prevalent in the neuropathic than in the non-neuropathic POTS group, suggesting more global differences between the two populations.
In relation to the ambiguous pathophysiological basis, there is no definitive treatment for POTS. There are reports of improvements in hemodynamic measures and symptoms of orthostatic tolerance with pharmacologic agents that include intravenous saline, intravenous phenylephrine, midodrine, octreotide, erythropoietin, pyridostigmine, and betablockade. The therapy is however frequently disappointing. Furthermore, there are no reported long-term studies of medications to treat POTS and there are no reports of the effects of any intervention on fatigue or quality of life.
The most widely used agents to treat POTS, the alpha-adrenoreceptor agonist midodrine, and the beta blockers, paradoxically have agonistic and antagonistic effects on the autonomic nervous system. Responses to these drugs are inconsistent and there are no delineated predictors of the response in POTS patients.
The comparison of therapeutic interventions in this protocol are based on the rationale that while alpha-adrenoreceptor agonists are thought to be more effective in neuropathic POTS - a disorder characterized by a compensatory increase in sympathetic outflow in which sympatholysis may be counterproductive, beta-adrenoreceptor antagonists are thought to be more effective in non-neuropathic POTS - a disorder that could be characterized by increased central sympathetic outflow due to impaired sympathetic inhibition.
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
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •CDC criteria for chronic fatigue syndrome
- •Evidence of postural tachycardia syndrome with symptoms of orthostatic intolerance
排除标准
- •Pregnant or lactating females. The administration of droxidopa is harmful to the fetus
- •Concomitant therapy with anticholinergic, alpha-, and beta-adrenergic antagonists or other medications that affect autonomic function
- •Clinically significant coronary artery, cerebrovascular or peripheral vascular disease
- •Cardiac arrhythmias
- •Systemic illness that might affect autonomic function such as congestive heart failure, hypertension, renal, pulmonary, and hepatic disease, anemia, malignancies, thyroid disease, and alcoholism
- •Severe depression, severe anxiety disorder (score of on the Beck Depression Inventory > 29 or score on the Beck Anxiety Inventory of ≥ 36) or psychosis
- •Antidepressant treatment by MAO inhibitors within 2 weeks before the study
- •Liver disease
- •Subjects with a history of reaction to local anesthetic will be excluded from the study
- •Subjects who have a history of any bleeding disorders or significantly impaired wound healing will be excluded. Subjects who are using any medications such as Coumadin or Plavix will be also excluded
- •Subjects who are currently enrolled in any other studies using investigational products
研究组 & 干预措施
Atenolol
In this arm subjects are randomized to atenolol 50 mg qd, droxidopa 100 mg/300 mg tid and placebo tid.
Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients.
Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.
干预措施: Droxidopa (Drug)
Atenolol
In this arm subjects are randomized to atenolol 50 mg qd, droxidopa 100 mg/300 mg tid and placebo tid.
Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients.
Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.
干预措施: Atenolol (Drug)
Atenolol
In this arm subjects are randomized to atenolol 50 mg qd, droxidopa 100 mg/300 mg tid and placebo tid.
Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients.
Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.
干预措施: Placebos (Drug)
Placebos
In this arm subjects are randomized to placebo tid.
Placebo is used to control the administration effect.
干预措施: Placebos (Drug)
Droxidopa
In this arm subjects are randomized to droxidopa 100 mg/300 mg tid, atenolol 50 mg qd, and placebo tid.
Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients.
Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.
干预措施: Droxidopa (Drug)
Droxidopa
In this arm subjects are randomized to droxidopa 100 mg/300 mg tid, atenolol 50 mg qd, and placebo tid.
Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients.
Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.
干预措施: Atenolol (Drug)
Droxidopa
In this arm subjects are randomized to droxidopa 100 mg/300 mg tid, atenolol 50 mg qd, and placebo tid.
Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients.
Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.
干预措施: Placebos (Drug)
结局指标
主要结局
Change Maximal Postural Tachycardia During Tilt
时间窗: 2 weeks after second intervention
Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.
Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline
时间窗: 2 weeks after second intervention
A 14 item self-report questionnaire. Subjects respond on a continuum of 1 to 4 questions evaluating fatigue intensity while distinguishing physical from mental fatigue.
Change in Maximal Postural Tachycardia During Tilt
时间窗: Up to 3 days after randomization
Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.
次要结局
- Change in Blood Pressure From Baseline(1 week after third intervention)
- Change in Heart Rate From Baseline(1 week after third intervention)
- Change in Vascular Resistance From Baseline(1 week after third intervention)
- Change in Muscle Sympathetic Nerve Activity From Baseline(1 week after third intervention)
- Change in Physical Functioning-SF-36 Q From Baseline(1 week after third intervention)
- Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline(1 week after third intervention)
- Change in Physical Functioning- HADS From Baseline(1 week after third intervention)
- Change in Physical Functioning-CIS From Baseline(1 week after third intervention)
- Change in Physical Functioning-MFI From Baseline(1 week after third intervention)
- Change in Physical Functioning-FSS From Baseline(1 week after third intervention)
- Change in Physical Functioning-EuroQOL From Baseline(1 week after third intervention)
- Change in Physical Functioning-OI From Baseline(1 week after third intervention)
研究者
Roy Freeman, MD
Professor of Neurology
Beth Israel Deaconess Medical Center