Open-Label Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH)

Study Overview
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Brief Summary
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The purpose of this study is to assess the durability of effect of Droxidopa in treating symptoms of neurogenic orthostatic hypotension in patients with Primary Autonomic Failure (Pure Autonomic Failure, Multiple System Atrophy, Parkinson's Disease), Non-diabetic neuropathy, or Beta Hydroxylase deficiency.

Detailed Description
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Systolic blood pressure is transiently and minimally decreased in healthy individuals upon standing. Normal physiologic feedback mechanisms work through neurally-mediated pathways to maintain the standing blood pressure, and thus maintain adequate cerebral perfusion. The compensatory mechanisms that regulate blood pressure upon standing are dysfunctional in subjects with orthostatic hypotension (OH), a condition that may lead to inadequate cerebral perfusion with accompanying symptoms of syncope, dizziness or lightheadedness, unsteadiness and blurred or impaired vision, among other symptoms. The autonomic nervous system has a central role in the regulation of blood pressure. Primary Autonomic Failure is manifested in a variety of syndromes. Orthostatic hypotension is a usual presenting symptom. Primary Autonomic Failure may be the primary diagnosis, and classifications include pure autonomic failure (PAF), also called idiopathic orthostatic hypotension (Bradbury-Eggleston syndrome) autonomic failure with multiple system atrophy (Shy-Drager syndrome) and also Parkinson's disease. Regardless of the primary condition, autonomic dysfunction underlies orthostatic hypotension. Orthostatic hypotension may be a severely disabling condition which can seriously interfere with the quality of life of afflicted subjects. Currently available therapeutic options provide some symptomatic relief in a subset of subjects, but are relatively ineffective and are often accompanied by severe side effects that limit their usefulness. Support garments (tight-fitting leotard) may prove useful in some subjects, but is difficult to don without family or nursing assistance, especially for older subjects. Midodrine, fludrocortisone, methylphenidate, ephedrine, indomethacin and dihydroergotamine are among some of the pharmacological interventions that have been used to treat orthostatic hypotension, although only midodrine is specifically approved for this indication. The limitations of these currently available therapeutic options, and the incapacitating nature and often progressive downhill course of disease, point to the need for an improved therapeutic alternative. The current withdrawal design study will measure the efficacy of droxidopa on symptoms of neurogenic orthostatic hypotension in patients randomized to continued droxidopa treatment versus placebo, following 14 days of double-blind treatment. Droxidopa Droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the International non-proprietary name (INN) for a synthetic amino acid precursor of norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co., Limited, Japan. It has been approved for use in Japan since 1989. Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Shy Drager syndrome (Multiple System Atrophy), Pure Autonomic Failure, and Parkinson's disease. There are four stereoisomers of DOPS; however, only the L-threo-enantiomer (droxidopa) is biologically active. The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been precisely defined; however, its NE replenishing properties with concomitant recovery of decreased noradrenergic activity are considered to be of major importance. Droxidopa has been marketed in Japan since 1989. Data from clinical studies and post-marketing surveillance programs conducted in Japan show that the most commonly reported adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In clinical studies, the prevalence and severity of droxidopa adverse effects appear to be similar to those reported by the placebo control arm.

Official Title
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An Open-label Study, to Assess the Long-term Safety and Clinical Benefit of Droxidopa in Subjects With PAF, Dopamine Beta Hydroxylase Deficiency or Non-diabetic Neuropathy and Symptomatic Neurogenic Orthostatic Hypotension

Conditions
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Neurogenic Orthostatic Hypotension, Non-Diabetic Autonomic Neuropathy, Multiple System Atrophy, Dopamine Beta Hydroxylase Deficiency

Intervention / Treatment
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* Drug: Droxidopa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for inclusion, each patient must fulfill the following criteria: Participated in Droxidopa Protocol 302; Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care. Exclusion Criteria: Patients are not eligible for this study if they fulfill one or more of the following criteria: Currently taking ephedrine or midodrine; Patients taking ephedrine or midodrine must stop taking these drugs at least 2 days prior to their study entry visit (Visit 1). Currently taking anti-hypertensive medication; * The use of short-acting anti-hypertensive medications at bedtime is permitted. Currently taking tri-cyclic antidepressant medication or other norepinephrine re-uptake inhibitors; Have changed dose, frequency and or type of prescribed medication, within two weeks of study start (excluding ephedrine and midodrine); History of more than moderate alcohol consumption; History of known or suspected drug or substance abuse; Women of childbearing potential who are not using a medically accepted contraception; Reproductive potential: Female subjects should be either post-menopausal (amenorrhea for at least 12 consecutive months), surgically sterile, or women of child-bearing potential (WOCP) who are using or agree to use acceptable methods of contraception. Acceptable contraceptives include intrauterine devices (IUDs), hormonal contraceptives (oral, depot, patch or injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam. For WOCP a urine pregnancy test must be conducted at each study visit. WOCP must be advised to use acceptable contraceptives throughout the study period and for 30 days after the last dose of investigational product. If hormonal contraceptives are used they should be taken according to the package insert. WOCP who are not currently sexually active must agree to use acceptable contraception, as defined above, if they decide to become sexually active during the period of the study and for 30 days after the last dose of investigational product. Sexually active males whose partner is a WOCP and who do not agree to use condoms for the duration of the study and for 30 days after the last dose; Women who are pregnant or breast feeding; Known or suspected hypersensitivity to the study medication or any of its ingredients; Pre-existing sustained severe hypertension (BP 180/110 mmHg in the sitting position); Have atrial fibrillation or, in the investigator's opinion, have any other significant cardiac arrhythmia; Any other significant systemic, hepatic, cardiac or renal illness; Diabetes mellitus or insipidus; Have a history of closed angle glaucoma; Have a known or suspected malignancy; Have a serum creatinine level > 130 umol/L; Patients with known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator's opinion, affect the absorption of study drug; In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing; In the investigator's opinion, are unable to adequately co-operate because of individual or family situation; In the investigator's opinion, are suffering from a mental disorder that interferes with the diagnosis and/or with the conduct of the study, e.g. schizophrenia, major depression, dementia; Are not able or willing to comply with the study requirements for the duration of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Droxidopa<br>Study medication | Drug: Droxidopa<br>* 100 mg, oral, three times per day 200 mg, oral, three times per day 300 mg, oral, three times per day 400 mg, oral, three times per day 500 mg, oral, three times per day 600 mg, oral, three times per day<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* 100 mg, oral, three times per day 200 mg, oral, three times per day 300 mg, oral, three times per day 400 mg, oral, three times per day 500 mg, oral, three times per day 600 mg, oral, three times per day<br>* Other names: Inactive drug (to look like Droxidopa);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Orthostatic Hypotension Questionnaire Composite Score (OHQ) | The OHQ is the average of two sub-scales, the Orthostatic Hypotension Symptom Assessment Scale (OHSA) and the Orthostatic Hypotension Daily Activities Scale (OHDAS). Each asks the patient to rate their symptoms or disease impact over the past week. The OHSA sub-scale is the average of six items: 1) Dizziness, lightheadedness, feeling faint or feeling like you might black out; 2) Problems with vision; 3) Weakness; 4) Fatigue; 5) Trouble concentrating; and 6) Head/neck discomfort. The OHDAS sub-scale is the average of four items: 1) Standing for a short time; 2) Standing for a long time; 3) Walking for a short time; and 4) Walking for a long time. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug). All patients are on open-label droxidopa for 3 months prior to randomization. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Orthostatic Hypotension Daily Activities (OHDAS) Score | The OHDAS scale is the average of four items: 1) Standing for a short time; 2) Standing for a long time; 3) Walking for a short time; and 4) Walking for a long time. Each asks the patient to rate their disease impact over the past week. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe. Change: score at end of randomization minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug). | 14 days | 
| Change in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score | The OHSA scale is the average of six items: 1) Dizziness, lightheadedness, feeling faint or feeling like you might black out; 2) Problems with vision; 3) Weakness; 4) Fatigue; 5) Trouble concentrating; and 6) Head/neck discomfort. Each asks the patient to rate their symptoms over the past week. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe. Change: score at end of randomization minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug). | 14 days | 
| Change in Systolic Blood Pressure (SBP) Measurements 3 Minutes Post Standing | Change: standing systolic blood pressure at end of study minus standing systolic blood pressure at randomization. In this withdrawal design, a negative score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug). All patients are on open-label droxidopa for 3 months prior to randomization to either continued droxidopa or to placebo. | 14 days | 
| Patient Reported Clinical Global Impression - Severity | The CGI-S is a 7 point scale ranging from a score of 1 (no symptoms) to 7 (severe symptoms). Patients were grouped according to OH severity at the end of the randomization period as follows; Normal-Borderline OH (CGI-S 1-2), Mild-Moderate OH (CGI-S 3-4), Marked OH-Most Ill with OH (CGI-S 5-7). . | 14 days | 
| Clinician Recorded Clinical Global Impression - Severity | The CGI-S is a 7 point scale ranging from a score of 1 (no symptoms) to 7 (severe symptoms). Patients were grouped according to OH severity at the end of the randomization period as follows; Normal-Borderline OH (CGI-S 1-2), Mild-Moderate OH (CGI-S 3-4), Marked OH-Most Ill with OH (CGI-S 5-7). | 14 days | 
| Patient Reported Clinical Global Impression - Improvement | The CGI-I is a 7 point scale ranging from a score of 1 (very much improved) to 7 (very much worse), with no change in the middle, and assesses the improvement in relation to the baseline evaluation. Patients will be grouped according change in disease as follows; Very Much Improved to Slightly Improved (CGI-I 1-3), No Change (CGI-I 4), Slightly Worse to Very Much Worse (CGI-I 5-7). | 14 days | 
| Clinician Rated Clinical Global Impressions - Improvement | The CGI-I is a 7 point scale ranging from a score of 1 (very much improved) to 7 (very much worse), with no change in the middle, and assesses the improvement in relation to the baseline evaluation. Patients will be grouped according change in disease as follows; Very Much Improved to Slightly Improved (CGI-I 1-3), No Change (CGI-I 4), Slightly Worse to Very Much Worse (CGI-I 5-7). | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NOH, Neurogenic Orthostatic Hypotension, Orthostatic hypotension, PAF, Pure Autonomic Failure, MSA, Multiple System Atrophy, Neuropathy, Autonomic Failure, Parkinson, Dopamine Deficiency, Dopamine, Droxidopa