NOH303: Open-Label Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH)

• Sponsor: Chelsea Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00738062
• Collaborator: (none)
• Enrollment: 103
• Locations: 54
• Arms: 2
• Duration (Months): 35
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Neurogenic Orthostatic Hypotension; Non-Diabetic Autonomic Neuropathy; Multiple System Atrophy; Dopamine Beta Hydroxylase Deficiency	Drug: Droxidopa; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Droxidopa Study medication	Drug: 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
Placebo Comparator: Placebo Placebo	Drug: 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; Other Names: Inactive drug (to look like Droxidopa)

Outcome Measures

Primary Outcome Measures

1. Change in Orthostatic Hypotension Questionnaire Composite Score (OHQ) [14 days]

   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.

Secondary Outcome Measures

1. Change in Orthostatic Hypotension Daily Activities (OHDAS) Score [14 days]

   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).

2. Change in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score [14 days]

   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).

3. Change in Systolic Blood Pressure (SBP) Measurements 3 Minutes Post Standing [14 days]

   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.

4. Patient Reported Clinical Global Impression - Severity [14 days]

   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). .

5. Clinician Recorded Clinical Global Impression - Severity [14 days]

   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).

6. Patient Reported Clinical Global Impression - Improvement [14 days]

   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).

7. Clinician Rated Clinical Global Impressions - Improvement [14 days]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Dedicated Clinical Research	Litchfield Park	Arizona	United States	85340
3	Xenoscience Inc.	Phoenix	Arizona	United States	85004
4	Sun Health Research Institute	Sun City	Arizona	United States	85351
5	The Parkinson's and Movement Disorders Institute	Fountain Valley	California	United States	92708
6	Pacific Neuroscience Medical Group	Oxnard	California	United States	93030
7	The Parkinson's Institute	Sunnyvale	California	United States	94085
8	Electrophysiology Associates	Colorado Springs	Colorado	United States	80910
9	Parkinson's Disease & Movment Disorder Center	Boca Raton	Florida	United States	33486
10	Southeastern Integrated Medical	Gainesville	Florida	United States	32607
11	Mayo Jacksonville Florida Department of Neurology	Jacksonville	Florida	United States	32224
12	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
13	University of South Florida	Tampa	Florida	United States	33606
14	Medical Associates of North Georgia	Canton	Georgia	United States	30114
15	Saint Mary of Nazareth Hospital Center	Chicago	Illinois	United States	60622
16	North Chicago VA Medical Center	North Chicago	Illinois	United States	60064
17	Indiana Medical Research	Elkhart	Indiana	United States	46514
18	JWM Neurology	Indianapolis	Indiana	United States	46237
19	Kansas City Bone and Joint, PA	Overland Park	Kansas	United States	66211
20	University of Louisville	Louisville	Kentucky	United States	40202
21	University of Maryland Hospital	Baltimore	Maryland	United States	21201
22	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
23	University of Massachusetts Worcester	Worcester	Massachusetts	United States	01655
24	Henry Ford Health System	Southfield	Michigan	United States	48034
25	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
26	Washington University Medical Center	St. Louis	Missouri	United States	63110
27	New Jersey Neuroscience Institute	Edison	New Jersey	United States	08818
28	Kingston Neurological Associates, PC	Kingston	New York	United States	12401
29	NYU Medical Center	New York City	New York	United States	10016
30	Columbia University Neurological institute of NY	New York	New York	United States	10032
31	University of Rochester	Rochester	New York	United States	14618
32	Duke University Medical Center	Durham	North Carolina	United States	27705
33	Wake Forest University	Winston Salem	North Carolina	United States	27157
34	University of Cincinnati	Cincinnati	Ohio	United States	45267
35	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
36	Cleveland Clinic	Cleveland	Ohio	United States	44195
37	COR Clinical Research, LLC	Oklahoma City	Oklahoma	United States	73103
38	The Oregon Clinic	Portland	Oregon	United States	97213
39	Vanderbilt University	Nashville	Tennessee	United States	37212
40	Jacinto Medical Group, PA	Baytown	Texas	United States	77521
41	UT Southwestern Medical Center	Dallas	Texas	United States	75390-9036
42	Scott & White Healthcare - Round Rock	Round Rock	Texas	United States	78665
43	Scott & White Memorial Hospital & Clinic	Temple	Texas	United States	76508
44	East Texas Medical Center - Neurological Institute Movment Disorders Center	Tyler	Texas	United States	75701
45	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
46	Baker Heart Research Institute	Melbourne	Victoria	Australia	3004
47	Austin Hospital	Heidelburg		Australia	3084
48	McMaster University	Hamilton	Ontario	Canada	L8L2X2
49	Centre for Movement Disorders	Markham	Ontario	Canada	L6B1C9
50	Parkinson's & Neurodegenerative Disorders Clinic	Ottawa	Ontario	Canada	K1G4G3
51	SMBD Jewish General Hospital - Department of Neurology	Montreal	Quebec	Canada	H3T 1E2
52	Quebec Memory and Motor Skills Disorders Clinic	Quebec		Canada	G1R 3X5
53	Auckland Hospital	Grafton Auckland	Private Bag	New Zealand
54	Van der Veer Institute for Parkinson's Disease and Movement Disorders	Christchurch		New Zealand

Sponsors and Collaborators

• Chelsea Therapeutics

Investigators

• Principal Investigator: Horacio Kaufmann Kaufmann, MD, NYU School of Medicine
• Principal Investigator: Christopher J. Mathias, MD, Imperial School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Chelsea Therapeutics
• ClinicalTrials.gov Identifier: NCT00738062
• Other Study ID Numbers: Droxidopa NOH303
• First Posted: Aug 20, 2008
• Last Update Posted: May 16, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Chelsea Therapeutics: NOH; Neurogenic Orthostatic Hypotension; Orthostatic hypotension; PAF; Pure Autonomic Failure; MSA; Multiple System Atrophy; Neuropathy; Autonomic Failure; Parkinson; Dopamine Deficiency; Dopamine; Droxidopa
• Additional relevant MeSH terms: Hypotension, Orthostatic; Multiple System Atrophy; Shy-Drager Syndrome; Autonomic Nervous System Diseases; Hypotension; Atrophy; Droxidopa

Study Results

Participant Flow

Arm/Group Title	Open-Label Droxidopa	Double-blind Droxidopa	Double-blind Placebo
Arm/Group Description	3 months of open-label treatment with droxidopa (t.i.d., at optimal dose)	Double-blind 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	Double-blind 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
Period Title: Open Label Treatment
STARTED	103	0	0
COMPLETED	75	0	0
NOT COMPLETED	28	0	0
Period Title: Open Label Treatment
STARTED	0	38	37
COMPLETED	0	38	37
NOT COMPLETED	0	0	0
Period Title: Open Label Treatment
STARTED	74	0	0
COMPLETED	57	0	0
NOT COMPLETED	17	0	0

Baseline Characteristics

Arm/Group Title	Open-Label Droxidopa	Double-blind Droxidopa	Double-blind Placebo	Total
Arm/Group Description	Only participated in 3 months of open-label treatment with droxidopa (t.i.d., at optimal dose)	Double-blind 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	Double-blind 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	Total of all reporting groups
Overall Participants	27	38	37	102
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (10.95)	68.2 (13.03)	66.2 (12.09)	65.8 (12.31)
Sex: Female, Male (Count of Participants)
Female	13 48.1%	15 39.5%	13 35.1%	41 40.2%
Male	14 51.9%	23 60.5%	24 64.9%	61 59.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 2.7%	1 1%
Asian	0 0%	1 2.6%	0 0%	1 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	27 100%	37 97.4%	36 97.3%	100 98%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	16 59.3%	25 65.8%	22 59.5%	63 61.8%
Canada	2 7.4%	6 15.8%	3 8.1%	11 10.8%
Australia	2 7.4%	2 5.3%	2 5.4%	6 5.9%
New Zealand	0 0%	1 2.6%	1 2.7%	2 2%
United Kingdom	0 0%	1 2.6%	3 8.1%	4 3.9%
Poland	7 25.9%	3 7.9%	6 16.2%	16 15.7%
Primary Clinical Diagnosis (participants) [Number]
Parkinson's Disease	10 37%	20 52.6%	18 48.6%	48 47.1%
Multiple System Atrophy	10 37%	8 21.1%	9 24.3%	27 26.5%
Pure Autonomic Failure	3 11.1%	8 21.1%	7 18.9%	18 17.6%
Dopamine Beta-Hydroxylase Deficiency	0 0%	1 2.6%	0 0%	1 1%
Non-Diabetic Autonomic Neuropathy	3 11.1%	0 0%	2 5.4%	5 4.9%
Other	1 3.7%	1 2.6%	1 2.7%	3 2.9%

Outcome Measures

1. Primary Outcome

Title	Change in Orthostatic Hypotension Questionnaire Composite Score (OHQ)
Description	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.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The analysis population was based on the ITT population of all patients randomized. Last observation carry forward was used for patients who prematurely discontinued the study. One droxidopa patient was excluded from the analysis because OHQ values were not evaluable.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	37	37
Mean (Standard Deviation) [units on a scale]	0.57 (1.891)	0.90 (1.550)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.438
	Comments
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at randomization.

2. Secondary Outcome

Title	Change in Orthostatic Hypotension Daily Activities (OHDAS) Score
Description	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).
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

One droxidopa patient excluded from analysis because data were not evaluable.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	37	37
Mean (Standard Deviation) [units on a scale]	0.53 (2.204)	0.71 (1.629)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.554
	Comments
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHDAS Composite value at randomization.

3. Secondary Outcome

Title	Change in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score
Description	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).
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Mean (Standard Deviation) [units on a scale]	0.59 (1.963)	1.10 (1.658)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.198
	Comments
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Composite value at baseline.

4. Secondary Outcome

Title	Change in Systolic Blood Pressure (SBP) Measurements 3 Minutes Post Standing
Description	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.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Mean (Standard Deviation) [mmHg]	-8.4 (26.63)	0.0 (18.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.286
	Comments
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at randomization.

5. Post-Hoc Outcome

Title	Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1)
Description	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study 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). All patients were on open-label droxidopa for 3 months prior to randomization to either continued droxidopa or to placebo.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Mean (Standard Deviation) [units on a scale]	0.9 (2.39)	1.3 (2.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.251
	Comments
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at randomization.

6. Secondary Outcome

Title	Patient Reported Clinical Global Impression - Severity
Description	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). .
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Normal-Borderline OH	13 48.1%	12 31.6%
Mild-Moderate OH	16 59.3%	13 34.2%
Marked OH-Most ill with OH	9 33.3%	12 31.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.708
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Clinician Recorded Clinical Global Impression - Severity
Description	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).
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Normal-Borderline OH	9 33.3%	7 18.4%
Mild-Moderate OH	16 59.3%	15 39.5%
Marked OH-Most ill with OH	13 48.1%	15 39.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.873
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Patient Reported Clinical Global Impression - Improvement
Description	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).
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Very much - Slightly Improved	25 92.6%	20 52.6%
No Change	7 25.9%	5 13.2%
Slightly - Very much Worse	6 22.2%	12 31.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.252
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Clinician Rated Clinical Global Impressions - Improvement
Description	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).
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	Study medication 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	Placebo 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
Measure Participants	38	37
Very much - Slightly Improved	26 96.3%	20 52.6%
No Change	4 14.8%	8 21.1%
Slightly - Very much Worse	8 29.6%	9 23.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.330
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Arm/Group Title	Three Month Open-Label Droxidopa		Double-blind Droxidopa		Double-blind Placebo		Long-Term Follow-up		Total Droxidopa
Arm/Group Description	all patients who participated in 3 months of open-label treatment with droxidopa (t.i.d., at optimal dose)		Double-blind 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		Double-blind 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		Open-label treatment with droxidopa (t.i.d) following the double-blind randomization phase.		All Patients exposed to droxidopa
All Cause Mortality
	Three Month Open-Label Droxidopa		Double-blind Droxidopa		Double-blind Placebo		Long-Term Follow-up		Total Droxidopa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Three Month Open-Label Droxidopa		Double-blind Droxidopa		Double-blind Placebo		Long-Term Follow-up		Total Droxidopa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/102 (11.8%)		1/38 (2.6%)		0/37 (0%)		16/74 (21.6%)		26/102 (25.5%)
Cardiac disorders
Angina pectoris	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	2/102 (2%)	2
Atrial fibrillation	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Coronary artery disease	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Ear and labyrinth disorders
Vertigo	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Gastrointestinal disorders
Diverticulum	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
General disorders
Sudden cardiac death	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Infections and infestations
Urinary tract infection	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	2/74 (2.7%)	2	2/102 (2%)	2
Pneumonia	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	2/74 (2.7%)	2	2/102 (2%)	2
Injury, poisoning and procedural complications
Contusion	0/102 (0%)	0	1/38 (2.6%)	1	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Facial bones fracture	0/102 (0%)	0	1/38 (2.6%)	1	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Fall	0/102 (0%)	0	1/38 (2.6%)	1	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Hip fracture	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	2/74 (2.7%)	2	3/102 (2.9%)	3
Cervical vertebral fracture	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Pelvic fracture	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Metabolism and nutrition disorders
Dehydration	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Osteoarthritis	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Nervous system disorders
Syncope	1/102 (1%)	1	1/38 (2.6%)	1	0/37 (0%)	0	2/74 (2.7%)	2	4/102 (3.9%)	4
Headache	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Hypoxic encephalopathy	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Loss of consciousness	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Dementia	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Psychiatric disorders
Agitation	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Anxiety	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Confusional state	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Depression	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Hallucination	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Hallucination, visual	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Major depression	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Post-traumatic stress disorder	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Renal and urinary disorders
Renal failure acute	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Bronchial haemorrhage	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Respiratory distress	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Surgical and medical procedures
Malignant tumour excision	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Vascular disorders
Venous thrombosis limb	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	0/74 (0%)	0	1/102 (1%)	1
Deep vein thrombosis	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Orthostatic hypotension	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	1/102 (1%)	1
Other (Not Including Serious) Adverse Events
	Three Month Open-Label Droxidopa		Double-blind Droxidopa		Double-blind Placebo		Long-Term Follow-up		Total Droxidopa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/102 (36.3%)		8/38 (21.1%)		4/37 (10.8%)		43/74 (58.1%)		62/102 (60.8%)
General disorders
Edema peripheral	0/102 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	4/74 (5.4%)	5	4/102 (3.9%)	5
Infections and infestations
Urinary Tract Infection	9/102 (8.8%)	10	2/38 (5.3%)	2	0/37 (0%)	0	11/74 (14.9%)	18	17/102 (16.7%)	31
Bacteriuria	2/102 (2%)	2	0/38 (0%)	0	0/37 (0%)	0	4/74 (5.4%)	4	5/102 (4.9%)	6
Upper respiratory tract infection	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	4/74 (5.4%)	4	5/102 (4.9%)	5
Injury, poisoning and procedural complications
Fall	7/102 (6.9%)	8	0/38 (0%)	0	1/37 (2.7%)	1	16/74 (21.6%)	20	20/102 (19.6%)	29
Musculoskeletal and connective tissue disorders
Back pain	4/102 (3.9%)	4	2/38 (5.3%)	2	0/37 (0%)	0	7/74 (9.5%)	8	11/102 (10.8%)	14
Muscle Spasms	2/102 (2%)	2	1/38 (2.6%)	1	0/37 (0%)	0	4/74 (5.4%)	4	7/102 (6.9%)	7
Neck Pain	3/102 (2.9%)	3	0/38 (0%)	0	0/37 (0%)	0	3/74 (4.1%)	3	6/102 (5.9%)	6
Nervous system disorders
Headache	5/102 (4.9%)	6	1/38 (2.6%)	1	2/37 (5.4%)	2	6/74 (8.1%)	6	13/102 (12.7%)	15
Syncope	4/102 (3.9%)	5	1/38 (2.6%)	2	0/37 (0%)	0	7/74 (9.5%)	9	10/102 (9.8%)	17
Dizziness	2/102 (2%)	2	1/38 (2.6%)	1	1/37 (2.7%)	1	5/74 (6.8%)	8	8/102 (7.8%)	12
Tremor	2/102 (2%)	2	0/38 (0%)	0	0/37 (0%)	0	4/74 (5.4%)	5	5/102 (4.9%)	7
Somnolence	5/102 (4.9%)	5	0/38 (0%)	0	0/37 (0%)	0	1/74 (1.4%)	1	6/102 (5.9%)	6
Psychiatric disorders
Insomnia	1/102 (1%)	1	0/38 (0%)	0	0/37 (0%)	0	4/74 (5.4%)	4	5/102 (4.9%)	5
Vascular disorders
Orthostatic hypotension	3/102 (2.9%)	4	0/38 (0%)	0	0/37 (0%)	0	3/74 (4.1%)	3	6/102 (5.9%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.