A Clinical Study for Patients With Neurogenic Orthostatic... | NCT00782340

NCT00782340

Status Module

Sponsor/Collaborators Module

Name	Class
Chiltern International Inc.	INDUSTRY

Oversight Module

Description Module

Detailed Description

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.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Droxidopa	Active Comparator	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	Drug: Droxidopa
Placebo	Placebo Comparator	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	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	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

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change in Orthostatic Hypotension Questionnaire 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. For the change from randomization, negative numbers represent improvement from randomization in OHQ score.	7 days

Secondary Outcomes

Measure	Description	Time Frame
Change in Ability to Conduct Activities of Daily Living Score (OHDAS Composite Score)	OHDAS composite scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A negative score indicates an improvement during the double-blind randomized phase relative to value at randomization.	7 days

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

To be eligible for inclusion, each patient must fulfill the following criteria:

Male or female and aged 18 years or over
Clinical diagnosis of orthostatic hypotension associated with Primary Autonomic Failure (PD, MSA and PAF), Dopamine Beta Hydroxylase Deficiency or Non-Diabetic Autonomic Neuropathies
A documented fall in systolic blood pressure of at least 20 mmHg, or in diastolic blood pressure of at least 10 mmHg, within 3 minutes after standing;
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:

Currently taking ephedrine or midodrine
Patients taking ephedrine or midodrine must stop taking these drugs at least 2 days prior to their baseline visit (Visit 2).
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
For WOCP a serum beta HCG pregnancy test must be conducted at screening, and a urine pregnancy test must be conducted at baseline and study termination; the results must be negative at screening and at baseline for the patient to receive study medication.
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 mmol/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
Have participated in another clinical trial with an investigational agent (including named patient or compassionate use protocol) within 4 weeks before the start of the study
Previous enrolment in the study.

Contacts/Locations Module

Overall Officials

Name	Affiliation	Role
Stephen Greer, MD	Arkansas Cardiology	Principal Investigator
Alberto Vasquez, MD	Suncoast Neuroscience	Principal Investigator
Richard Hull, MD	North Alabama Neuroscience	Principal Investigator
Brent Goodman, MD	Mayo Clinic	Principal Investigator
Alvin McElveen, MD	Bradenton Neurology, Inc	Principal Investigator
Mazen Dimachkie, MD	University of Kansas Medical Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
North Alabama Neuroscience		Huntsville	Alabama	35801	United States
Mayo Clinic-Arizona

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
28494751	Derived	Biaggioni I, Arthur Hewitt L, Rowse GJ, Kaufmann H. Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension. BMC Neurol. 2017 May 12;17(1):90. doi: 10.1186/s12883-017-0867-5.
27538531	Derived	Francois C, Rowse GJ, Hewitt LA, Vo P, Hauser RA. Analysis of number needed to treat for droxidopa in patients with symptomatic neurogenic orthostatic hypotension. BMC Neurol. 2016 Aug 18;16(1):143. doi: 10.1186/s12883-016-0665-5.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Open-Label Titration	All patients titrated to their optimal dose of droxidopa for up to 2 weeks during open-label dose titration.
FG001	Droxidopa	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 Droxidopa: 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

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Not Randomized	Patients entered open label droxidopa dose titration, but did not proceed into washout and randomization.
BG001	Droxidopa	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 Droxidopa: 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
BG002	Placebo	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 Placebo: 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
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00064.6± 15.4 BG00157.4± 16.90 BG00255.7± 20.03 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00037 BG00140 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG00048 BG00133 BG002

Primary Clinical Diagnosis

Number

participants

Title

Denominators

Categories

Parkinson's Disease

Title	Measurements
	BG00045 BG00135 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change in Orthostatic Hypotension Questionnaire 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.

For the change from randomization, negative numbers represent improvement from randomization in OHQ score.

Missing data are imputed using the last observation carried forward method.

Posted

Mean

Standard Deviation

units on a scale

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Units	Counts
Participants	OG00082 OG00180

Title

Denominators

Categories

Title	Measurements
	OG000-1.83± 2.067 OG001-0.93± 1.691

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANCOVA	ANCOVA model that includes treatment as a factor and baseline OHQ composite score as a co-variate.	0.003	Statistical analysis plan involved a hierarchical assessment of secondary endpoints to prevent inflation of type I errors.												No	Superiority or Other

Secondary

Change in Ability to Conduct Activities of Daily Living Score (OHDAS Composite Score)

OHDAS composite scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A negative score indicates an improvement during the double-blind randomized phase relative to value at randomization.

Missing data are imputed using the last observation carried forward method.

Posted

Mean

Standard Deviation

units on a scale

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

Change in Orthostatic Hypotension Symptom Assessment (OHSA Composite) Score

OHSA composite scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A negative score indicates an improvement during the double-blind randomized phase relative to value at randomization.

Missing data are imputed using the last observation carried forward method.

Posted

Mean

Standard Deviation

units on a scale

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

Change in Activities Involving Standing a Short Time (OHDAS Item 1)

OHDAS Item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A negative score indicates an improvement during the double-blind randomized phase relative to value at randomization.

Missing data are imputed using the last observation carried forward method.

Posted

Mean

Standard Deviation

units on a scale

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

Change in Activities Involving Walking a Short Time (OHDAS Item 3)

OHDAS Item 3 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A negative score indicates an improvement during the double-blind randomized phase relative to value at randomization.

Missing data are imputed using the last observation carried forward method.

Posted

Mean

Standard Deviation

units on a scale

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1)

OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A negative score indicates an improvement during the double-blind randomized phase relative to value at randomization.

Missing data are imputed using the last observation carried forward method.

Posted

Mean

Standard Deviation

units on a scale

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

Patient-Reported Clinical Global Improvement - Severity Scores

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).

Posted

Number

participants

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

Clinician-Reported Clinical Global Improvement - Severity Scores

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).

Posted

Number

participants

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Secondary

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. A positive score indicates an improvement during the double-blind randomized phase relative to value at randomization.

Posted

Mean

Standard Deviation

mmHg

7 days

ID	Title	Description
OG000	Droxidopa	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 Droxidopa: 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
OG001	Placebo	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 Placebo: 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

Units

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Open-Label Titration	All patients treated with study drug during dose titration (7-14 days)	2	263	38	263
EG001	Droxidopa	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 Droxidopa: 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	0	81	9	81
EG002	Placebo	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 Placebo: 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	0	81	1	81

Serious Adverse Events

Term	Organ System	Statistical Information
Nausea	Gastrointestinal disorders	EG0001 events1 affected263 at risk EG0010 events0 affected81 at risk EG0020 events0 affected81 at risk
Vomiting	Gastrointestinal disorders	EG0001 events1 affected263 at risk EG0010 events0 affected81 at risk EG0020 events0 affected81 at risk
Urinary Tract Infection	Infections and infestations	EG0001 events1 affected263 at risk EG0010 events0 affected81 at risk EG0020 events0 affected81 at risk
Neurogenic bladder	Renal and urinary disorders	EG0001 events1 affected263 at risk EG0010 events0 affected81 at risk EG0020 events0 affected81 at risk
Ureteric obstruction	Renal and urinary disorders	EG0001 events1 affected263 at risk EG0010 events0 affected81 at risk EG0020 events0 affected81 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Headache	Nervous system disorders				EG00034 events26 affected263 at risk EG0017 events6 affected81 at risk EG0020 events0 affected81 at risk
Dizziness	Nervous system disorders				EG00018 events17 affected263 at risk EG0013 events3 affected81 at risk EG0021 events1 affected81 at risk

ID	Term
C535600	dopamine beta hydroxylase deficiency
D007024	Hypotension, Orthostatic
D054970	Pure Autonomic Failure
D019578	Multiple System Atrophy

Ancestor Terms

ID	Term
D054971	Orthostatic Intolerance
D054969	Primary Dysautonomias
D001342	Autonomic Nervous System Diseases
D009422	Nervous System Diseases
D007022	Hypotension
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D001480	Basal Ganglia Diseases
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009069	Movement Disorders
D000080874	Synucleinopathies
D019636	Neurodegenerative Diseases

ID	Term
D015103	Droxidopa

Ancestor Terms

ID	Term
D009638	Norepinephrine
D002395	Catecholamines
D000588	Amines
D009930	Organic Chemicals
D002396	Catechols
D010636	Phenols
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D012694	Serine
D021542	Amino Acids, Neutral
D000596	Amino Acids
D000602	Amino Acids, Peptides, and Proteins

Units	Counts
Participants	OG00081 OG00179

Units	Counts
Participants	OG00081 OG00179

Units	Counts
Participants	OG00082 OG00180

Units	Counts
Participants	OG00082 OG00180

Units	Counts
Participants	OG00082 OG00180