A Two Part Study (306A/306B) to Assess Droxidopa in Treatment of NOH in Patients With Parkinson's Disease

• Sponsor: Chelsea Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01176240
• Collaborator: (none)
• Enrollment: 225
• Locations: 60
• Arms: 2
• Duration (Months): 29
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a study to evaluate the effects of an investigational drug, Droxidopa, in participants with neurogenic orthostatic hypotension (NOH), associated with Parkinson's disease. Droxidopa is being studied to determine the effects on blood pressure changes upon standing up (orthostatic challenge). Symptoms and activity measurements, including patient reported falls, will be evaluated to determine the effectiveness of the study drug.

Symptoms of NOH may include any of the following:

• Dizziness, light-headedness, feeling faint or feeling like you may blackout

• Problems with vision (blurring, seeing spots, tunnel vision, etc.)

• Weakness

• Fatigue

• Trouble concentrating

• Head & neck discomfort (the coat hanger syndrome)

• Difficulty standing for a short time or a long time

• Trouble walking for a short time or a long time

The study duration is a maximum of approximately 14 weeks including up to 2 weeks for screening, up to 2 weeks for proper dose finding, followed by an 8 week treatment period and a follow-up visit after 2 weeks. A sufficient number of patients will be screened to allow approximately 211 randomized patients. An extension study is also available to continue treatment if determined appropriate by the study doctor. This Study is NCT01132326 sponsored by Chelsea Therapeutics and is enrolling by invitation only.

Condition or Disease	Intervention/Treatment	Phase
Orthostatic Hypotension; Parkinson's Disease	Drug: Droxidopa; Other: 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.

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.

Symptomatic OH in patients with Parkinson's disease is thought to be a consequence of norepinephrine depletion leading to low systolic blood pressure (SBP) and cerebral-hypoperfusion (reduced blood flow to the brain). Therapy with droxidopa results in increased levels of norepinephrine which should lead to improved SBP and cerebral perfusion thereby reducing the signs and symptoms of NOH. The present study will evaluate the clinical benefit in NOH patients with PD treated with droxidopa compared to those treated with placebo.

Participation in the study will last a maximum of 14 weeks consisting of a 2 week (maximum) screening/baseline period; a 2 week (maximum) double-blind dose titration; an 8 week double-blind placebo-controlled treatment period; and a 2 week follow-up period. An extension study is also available to continue treatment if determined appropriate by the study doctor. This Study is NCT01132326 sponsored by Chelsea Therapeutics and is enrolling by invitation only.

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. Stereoisomers and enantiomers are compounds that have the same chemical elements; however, they may react differently as the elements are positioned in different locations.

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: 225 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Double-blind, Randomized, Parallel-Group, Placebo-Controlled Study to Assess the Clinical Effect of Droxidopa in the Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Patients With Parkinson's Disease
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Droxidopa droxidopa active drug	Drug: Droxidopa; 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment; Other Names: Northera L-DOPS L-threo-dihydroxyphenylserine SM-5688
Placebo Comparator: Placebo Placebo matched control	Other: Placebo; Placebo; Other Names: Mannitol, Sugar Pill

Outcome Measures

Primary Outcome Measures

1. 306A Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ) [Baseline, Week 8]

   The primary efficacy endpoint for 306A is the relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. 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 baseline, negative numbers represent improvement from baseline in OHQ score.

2. 306B Efficacy: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1) [Baseline, Week1]

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

Secondary Outcome Measures

1. 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5) [Baseline, Week2]

   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 2 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.

2. 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6) [Baseline, Week4]

   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 4 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.

3. 306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to Week 1 [Baseline, Week 1]

   Measure: Lowest standing systolic blood pressure reading of immediately post standing and 3 minutes post standing. Change: standing systolic blood pressure at Week 1 (Visit 4) minus standing systolic blood pressure at baseline. A positive score indicates an improvement in standing systolic blood pressure during the double-blind randomized phase relative to value at baseline.

4. 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7) [Baseline, Week 8]

   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 8 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.

5. 306B Efficacy: Rate of Patient Reported Falls [up to 10 weeks]

   The average number of patient reported falls per week.

6. 306B Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ) [Baseline, Week 8]

   The relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. 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 baseline, negative numbers represent improvement from baseline in OHQ score.

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. 18 years or over

2. Clinical diagnosis of Parkinson's disease

3. Clinical diagnosis of symptomatic neurogenic orthostatic hypotension

At their baseline visit (Visit 2), patients must demonstrate:

• a score of at least 3 or greater on the OHQ composite

• a score of at least 3 or greater on the clinician CGI-S

• a fall of at least 20 mmHg in their systolic blood pressure, or 10 mmHg in their diastolic blood pressure, within 3 minutes of standing 4. 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:

1. Score of 23 or lower on the mini-mental state examination (MMSE)

2. Concomitant use of vasoconstricting agents for the purpose of increasing blood pressure;

• Patients taking vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine must stop taking these drugs at least 2 days or 5 half-lives (whichever is longer) prior to their baseline visit (Visit 2) and throughout the duration of the study

1. Concomitant use of anti-hypertensive medication for the treatment of essential hypertension

2. Have changed dose, frequency or type of prescribed medication, within two weeks of baseline visit (Visit 2) with the following exceptions:

• Vasoconstricting agents such a ephedrine, dihydroergotamine, or midodrine

• Short courses (less than 2 weeks) of medications or treatments that do not interfere with, or exacerbate the patient's condition under study (e.g. antibiotics)

1. Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV definition of alcohol or substance abuse)

2. Women who are pregnant or breastfeeding

3. Women of child bearing potential (WOCP) who are not using at least one method of contraception with their partner

4. Male patients who are sexually active with a woman of child bearing potential (WOCP) and not using at least one method of contraception

5. Untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the patient

6. Sustained severe hypertension (BP ≥ 180 mmHg systolic or ≥ 110 mmHg diastolic in the seated or supine position which is observed in 3 consecutive measurements over an hour)

7. Any significant uncontrolled cardiac arrhythmia

8. History of myocardial infarction, within the past 2 years

9. Current unstable angina

10. Congestive heart failure (NYHA Class 3 or 4)

11. Diabetic autonomic neuropathy

12. History of cancer within the past 2 years other than a successfully treated, non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ

13. Gastrointestinal condition, which in the Investigator's judgment, may affect the absorption of study drug (e.g. ulcerative colitis, gastric bypass)

14. Any major surgical procedure within 30 days of the baseline visit (Visit 2)

15. Previously treated with droxidopa

16. Currently receiving any investigational drug or have received an investigational drug within 30 days of the baseline visit (Visit 2)

17. Any condition or laboratory test result, which in the Investigator's judgment, might result in an increased risk to the patient, or would affect their participation in the study. Additionally the Investigator has the ability to exclude a patient if for any reason they feel the subject is not a good candidate for the study or will not be able to follow study procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neurology Neurodiagnostic Lab	Alabaster	Alabama	United States	35007
2	Neurological Physicians of Arizona	Gilbert	Arizona	United States	85234
3	Xenoscience	Phoenix	Arizona	United States	85004
4	Barrow Neurology Clinic	Phoenix	Arizona	United States	85013
5	Banner Health	Sun City	Arizona	United States	85351
6	Center for Neurosciences	Tucson	Arizona	United States	85718
7	Northwest Neuro Specialists P.L.L.C.	Tucson	Arizona	United States	85741
8	Caring Clinical Research Incorporated	Laguna Hills	California	United States	92653
9	Hoag Memorial Hospital, Presbyterian	Newport Beach	California	United States	92663
10	Neurosearch - Pasadena	Pasadena	California	United States	91105
11	Alliance Clinical Research, LLC	Poway	California	United States	92064
12	Neurosearch, Inc.	Reseda	California	United States	91335
13	Neurosearch II, Inc.	Ventura	California	United States	93003
14	Neurology Consultants Medical Group	Whittier	California	United States	90606
15	Associated Neurologist of Southern Connecticut, PC	Fairfield	Connecticut	United States	06824
16	Hartford Hospital	Hartford	Connecticut	United States	06106
17	Eastern Connecticut Neurology Specialists	Manchester	Connecticut	United States	06040
18	Parkinson's Disease & Movement Disorder Disoder	Boca Raton	Florida	United States	33486
19	Pharmax Research Clinic, LLC	Miami	Florida	United States	33126
20	Neurology Associates of Ormond Beach	Ormond Beach	Florida	United States	32174
21	Neurostudies Inc.	Port Charlotte	Florida	United States	33952
22	Parkinson's Disease Treatment Center of Southwest Florida	Port Charlotte	Florida	United States	33980
23	Lovelace Scientific Research	Sarasota	Florida	United States	34233
24	Tampa General University of South Florida	Tampa	Florida	United States	33606
25	Vero Neurology	Vero Beach	Florida	United States	32960
26	Premiere Research Institute	West Palm Beach	Florida	United States	33407
27	Emory University	Atlanta	Georgia	United States	30329
28	Neurology Specialists of Decatur Research Center	Decatur	Georgia	United States	30033
29	Prism Research Group	Rome	Georgia	United States	30165
30	Alexian Brothers Hospital Network	Elk Grove Village	Illinois	United States	60007
31	Precise Clinical Research	Topeka	Kansas	United States	66604
32	North Oaks Health System	Hammond	Louisiana	United States	70403
33	Harvard Vanguard Medical Associates	Boston	Massachusetts	United States	02215
34	Detroit Clinical Research Center	Novi	Michigan	United States	48377
35	Northern Michigan Neurology	Traverse City	Michigan	United States	49684
36	Gulf Coast Neurology Center, PLLC	Ocean Springs	Mississippi	United States	39564
37	University of Nevada School of Medicine	Las Vegas	Nevada	United States	89102
38	Wellness and Research Center	Belvidere	New Jersey	United States	07823
39	AdvanceMed Research	Lawrenceville	New Jersey	United States	08648
40	Shore Neurology	Toms River	New Jersey	United States	08755
41	Upstate Clinical Research, LLC	Albany	New York	United States	12205
42	David L. Kreitzman, M.D., PC	Commack	New York	United States	11725
43	Kingston Neurological Associates	Kingston	New York	United States	12401
44	Parker Jewish Institute For Health Care and Rehabilitation Foundation	New Hyde Park	New York	United States	11040-1433
45	Beth Israel Medical Center	New York	New York	United States	10003
46	New York University	New York	New York	United States	10016
47	Neurological Care of CNY	Syracuse	New York	United States	13210
48	Asheville Neurology Specialists, PA	Asheville	North Carolina	United States	28806
49	Guilford Neurologic Associates	Greensboro	North Carolina	United States	27405
50	Clinical Trials of America Inc	Winston-Salem	North Carolina	United States	27103
51	Community Research	Cincinnati	Ohio	United States	45227
52	Ohio State University Medical Center	Columbus	Ohio	United States	43210
53	University of Toledo	Toledo	Ohio	United States	43614
54	Movement Disorder Clinic of Oklahoma PLLC	Tulsa	Oklahoma	United States	74136
55	Ilumina Clinical Associates	Johnstown	Pennsylvania	United States	15904
56	Clinical Trials Research Services LLC	Pittsburgh	Pennsylvania	United States	15206
57	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390-9063
58	JM Neuroscience Research	Salt Lake City	Utah	United States	84108
59	Neurological Associates, Inc.	Richmond	Virginia	United States	23226
60	Sentara Neurology Specialists	Virginia Beach	Virginia	United States	23456

Sponsors and Collaborators

• Chelsea Therapeutics

Investigators

• Principal Investigator: Robert Hauser, M.D., University of South Florida
• Study Chair: Lawrence A. Hewitt, Ph.D., Chelsea Therapeutics, Inc.
• Study Director: William Schwieterman, M.D., Chelsea Therapeutics, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Birkmayer W, Birkmayer G, Lechner H, Riederer P. DL-3,4-threo-DOPS in Parkinson's disease: effects on orthostatic hypotension and dizziness. J Neural Transm. 1983;58(3-4):305-13.
• Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension. 2003 Aug;42(2):136-42. Epub 2003 Jun 30. Erratum in: Hypertension. 2003 Oct;43(4):e12.
• Kachi T, Iwase S, Mano T, Saito M, Kunimoto M, Sobue I. Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activities in Shy-Drager syndrome. Neurology. 1988 Jul;38(7):1091-4.
• Kaufmann H, Saadia D, Voustianiouk A, Goldstein DS, Holmes C, Yahr MD, Nardin R, Freeman R. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 2003 Aug 12;108(6):724-8. Epub 2003 Jul 28.
• Malamut, R., Freeman, R., Gilden, J., Tulloch, J., Kaufmann, H., 2005. A multi-center, double-blind, randomized, placebo controlled, cross-over study to assess the clinical benefit of midodrine in patients with neurogenic orthostatic hypotension. Clin. Auto. Res. 15 (5) 337[abstract].
• Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease. The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003 Jul;18(7):738-50. Review.
• Narabayashi, H., Nakanishi, T., Kanazawa, I., Yoshida, M., Mizuno, Y., Yanagisawa, N., Kondo, T. 1987. Clinical effects of L-threo-3,4-dihydroxyphenylserine in Parkinson's disease and Parkinson syndrome: Results of multi-center open study at 45 institutions. Yakuri To Chiryo (Jpn. Pharmacol. Ther.) 15(Suppl. 2):411 to 443.
• Sobue, I., Senda, Y., Suzuki, T., Narabayashi, I., Hirayama, K. 1987. Clinical effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in Shy-Drager Syndrome and its related diseases. Shinkei Naika Chiryo [Neurol. Ther.] 4(2):199-208.
• Yanagisawa N, Ikeda S, Hashimoto T, Hanyu N, Nakagawa S, Fujimori N, Ushiyama M. [Effects of L-threo-Dops on orthostatic hypotension in Parkinson's disease]. No To Shinkei. 1998 Feb;50(2):157-63. Japanese.

• Responsible Party: Chelsea Therapeutics
• ClinicalTrials.gov Identifier: NCT01176240
• Other Study ID Numbers: Droxidopa NOH306 (306A / 306B)
• First Posted: Aug 5, 2010
• Last Update Posted: May 20, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Chelsea Therapeutics: lightheadedness; unsteadiness; dizziness; weak; fatigue; concentration; head & neck pain; standing/walking for a short time; standing/walking for a long time; Neurogenic Orthostatic Hypotension; falls; NOH; Parkinson's disease; weakness
• Additional relevant MeSH terms: Parkinson Disease; Hypotension, Orthostatic; Hypotension; Mannitol; Droxidopa

Study Results

Participant Flow

Pre-assignment Detail	Post-randomization, up to 2 weeks dose titration followed by 8 wks at optimal dose. The first 51 patients enrolled in the study were analyzed as a separate group in an interim analysis (Study 306A). The final 171 patients remained blinded until the end of the study and analyzed as a separate study (Study 306B).

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Period Title: Study 306A
STARTED	24	27
COMPLETED	21	24
NOT COMPLETED	3	3
Period Title: Study 306A
STARTED	89	85
Took at Least 1 Dose of Study Drug	87	84
1 wk of Stable Dosing and Visit 4	69	78
2 wk of Stable Dosing and Visit 5	68	75
4 wk of Stable Dosing and Visit 6	67	73
COMPLETED	63	68
NOT COMPLETED	26	17

Baseline Characteristics

Arm/Group Title	Study 306A: Droxidopa	Study 306A: Placebo	Study 306B: Droxidopa	Study 306B: Placebo	Total
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo	Total of all reporting groups
Overall Participants	24	27	87	84	222
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.2 (7.30)	72.9 (7.76)	72.5 (7.64)	72.2 (7.97)	72.4 (7.78)
Sex: Female, Male (Count of Participants)
Female	10 41.7%	10 37%	27 31%	30 35.7%	77 34.7%
Male	14 58.3%	17 63%	60 69%	54 64.3%	145 65.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 1.1%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	2 7.4%	2 2.3%	1 1.2%	5 2.3%
White	24 100%	25 92.6%	84 96.6%	83 98.8%	216 97.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%	27 100%	87 100%	84 100%	222 100%

Outcome Measures

1. Primary Outcome

Title	306A Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
Description	The primary efficacy endpoint for 306A is the relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. 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 baseline, negative numbers represent improvement from baseline in OHQ score.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

LOCF was used to impute values for patients who did not have an end of study visit.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	24	27
Mean (Standard Deviation) [units on a scale]	-2.2 (2.44)	-2.1 (2.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa, Placebo
	Comments	Study 306A was initially designed as a blinded interim analysis by an independent DMC to ensure that the overall study was adequately powered. Study 306A was not powered to provide statistical significance as a stand alone study. Thus, no additional efficacy end points were prospectively defined beyond the primary end point.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.978
	Comments
	Method	ANCOVA
	Comments	ANCOVA model that includes treatment as a factor and baseline OHQ composite score as a co-variate.

2. Primary Outcome

Title	306B Efficacy: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1)
Description	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 1 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame	Baseline, Week1

Outcome Measure Data

Analysis Population Description

The primary analysis was defined as those patients who completed 1 week of dosing at the identified optimal dose of study medication and completed the visit 4 (1 week) efficacy evaluation. Patients who did not have week 1 efficacy data were excluded from the analysis.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	69	78
Mean (Standard Deviation) [units on a scale]	-2.3 (2.95)	-1.3 (3.16)

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	0.018
	Comments	Statistical analysis plan involved a hierarchical assessment of secondary endpoints to prevent inflation of type I errors.
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at baseline.

3. Post-Hoc Outcome

Title	306A Efficacy: Patient Reported Falls
Description	The total number of patient reported falls during the 8 week treatment period
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	24	27
Number [total falls per group]	79	192

4. Secondary Outcome

Title	306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5)
Description	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 2 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame	Baseline, Week2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	68	75
Mean (Standard Deviation) [units on a scale]	-1.9 (2.86)	-1.6 (2.97)

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	0.60
	Comments	Statistical analysis plan involved a hierarchical assessment of secondary endpoints to prevent inflation of type I errors. As the first secondary endpoint was not positive, statistical analysis was not performed on additional secondary endpoints.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at baseline.

5. Secondary Outcome

Title	306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6)
Description	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 4 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame	Baseline, Week4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	67	73
Mean (Standard Deviation) [units on a scale]	-2.0 (3.08)	-1.5 (2.74)

6. Secondary Outcome

Title	306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to Week 1
Description	Measure: Lowest standing systolic blood pressure reading of immediately post standing and 3 minutes post standing. Change: standing systolic blood pressure at Week 1 (Visit 4) minus standing systolic blood pressure at baseline. A positive score indicates an improvement in standing systolic blood pressure during the double-blind randomized phase relative to value at baseline.
Time Frame	Baseline, Week 1

Outcome Measure Data

Analysis Population Description

One droxidopa patient did not complete the standing blood pressure measurements of the orthostatic standing test at visit 4 (one week of stable dosing)

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	68	78
Mean (Standard Deviation) [mmHg]	6.4 (18.85)	0.7 (20.18)

7. Secondary Outcome

Title	306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7)
Description	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 8 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

The analysis was defined as those patients who completed 8 week of dosing and completed the visit 7 (8 week) efficacy evaluation. Patients who did not have week 8 efficacy data were excluded from the analysis. Of note, 2 patients completed the 8 week double blind study, but did not complete the efficacy evaluations at the final visit.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	63	68
Mean (Standard Deviation) [units on a scale]	-2.1 (3.03)	-1.5 (2.91)

8. Secondary Outcome

Title	306B Efficacy: Rate of Patient Reported Falls
Description	The average number of patient reported falls per week.
Time Frame	up to 10 weeks

Outcome Measure Data

Analysis Population Description

The primary analysis was defined as those patients who completed 1 week of dosing at the identified optimal dose of study medication and completed the visit 4 (1 week) efficacy evaluation. Patients who did not have week 1 efficacy data were excluded from the analysis.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	69	78
Mean (Standard Deviation) [falls per week]	0.4 (0.84)	2.0 (12.95)

9. Secondary Outcome

Title	306B Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
Description	The relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. 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 baseline, negative numbers represent improvement from baseline in OHQ score.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

The primary analysis was defined as those patients who completed 8 week of dosing and completed the visit 7 (8 week) efficacy evaluation. Patients who did not have week 8 efficacy data were excluded from the analysis. Of note, 2 patients completed the 8 week double blind study, but did not complete the efficacy evaluations at the final visit.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	63	68
Mean (Standard Deviation) [units on a scale]	-2.2 (2.29)	-2.0 (2.18)

10. Post-Hoc Outcome

Title	Study 306A: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1) From Baseline to Week 1
Description	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 1 minus score at baseline. A negative score indicates improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame	Baseline, Week 1

Outcome Measure Data

Analysis Population Description

Last observation carried forward was used to impute missing values.

Arm/Group Title	Droxidopa	Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment	Placebo matched control Placebo: Placebo
Measure Participants	24	27
Mean (Standard Deviation) [units on a scale]	-3.1 (3.39)	-1.6 (3.12)

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	0.238
	Comments
	Method	ANCOVA
	Comments	ANCOVA model that includes treatment as a factor and baseline OHQ composite score as a co-variate.

Adverse Events

Adverse Event Reporting Description	Subjects with more than 1 of a given AE, the subject is counted only once for that AE. Subject with more than one AE in a system organ class (SOC), the subject is counted only once in that SOC. Only dosed patients included in Safety Set. Droxidopa Safety Set includes 3 patients randomized to placebo who were mistakenly dosed with droxidopa.
Arm/Group Title	Droxidopa		Placebo
Arm/Group Description	droxidopa active drug Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment Droxidopa Safety set includes 3 patients randomized to placebo who were mistakenly dosed with droxidopa for short periods of time during the trial.		Placebo matched control Placebo: Placebo Placebo Safety set excludes 3 patients randomized to placebo who were mistakenly dosed with droxidopa for short periods of time during the trial.
All Cause Mortality
	Droxidopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Droxidopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/114 (4.4%)		4/108 (3.7%)
Cardiac disorders
Atrial fibrillation	1/114 (0.9%)	1	0/108 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/114 (0.9%)	1	0/108 (0%)	0
Faecaloma	1/114 (0.9%)	1	0/108 (0%)	0
Inguinal hernia	1/114 (0.9%)	1	0/108 (0%)	0
General disorders
Asthenia	0/114 (0%)	0	1/108 (0.9%)	1
Infections and infestations
Bronchitis viral	1/114 (0.9%)	1	0/108 (0%)	0
Upper respiratory tract infection bacterial	1/114 (0.9%)	1	0/108 (0%)	0
Viral infection	0/114 (0%)	0	1/108 (0.9%)	1
Injury, poisoning and procedural complications
Fibula fracture	0/114 (0%)	0	1/108 (0.9%)	1
Nervous system disorders
Presyncope	1/114 (0.9%)	1	0/108 (0%)	0
Syncope	0/114 (0%)	0	2/108 (1.9%)	2
Psychiatric disorders
Mental status changes	1/114 (0.9%)	1	0/108 (0%)	0
Vascular disorders
Hypertension	1/114 (0.9%)	1	0/108 (0%)	0
Other (Not Including Serious) Adverse Events
	Droxidopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/114 (47.4%)		52/108 (48.1%)
Gastrointestinal disorders
Nausea	10/114 (8.8%)	13	5/108 (4.6%)	5
Diarrhoea	4/114 (3.5%)	4	8/108 (7.4%)	9
General disorders
Fatigue	8/114 (7%)	8	6/108 (5.6%)	7
Oedema peripheral	5/114 (4.4%)	5	6/108 (5.6%)	6
Injury, poisoning and procedural complications
Contusion	6/114 (5.3%)	7	12/108 (11.1%)	14
Excoriation	6/114 (5.3%)	6	8/108 (7.4%)	8
Skin laceration	5/114 (4.4%)	10	10/108 (9.3%)	15
Investigations
Blood pressure increased	4/114 (3.5%)	9	7/108 (6.5%)	7
Nervous system disorders
Headache	15/114 (13.2%)	19	8/108 (7.4%)	8
Dizziness	11/114 (9.6%)	13	5/108 (4.6%)	6
Vascular disorders
Hypertension	7/114 (6.1%)	10	1/108 (0.9%)	2

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.