Dose Response to the Norepinephrine Precursor Droxidopa i... | NCT03602014

Status Module

Name	Class
New York State Department of Health	OTHER_GOV

Description Module

Detailed Description

Interruption of sympathetic cardiovascular autonomic regulation following spinal cord injury (SCI) is associated with significantly reduced plasma norepinephrine (NE) levels, hypotension and orthostatic hypotension (OH), particularly in individuals with high cord lesions. Although the incidence of hypotension is reported to be as high as 70% in persons with cervical lesions (i.e., tetraplegia), the vast majority of these individuals remains asymptomatic and, therefore, does not raise clinical concern, or prompt intervention. While it is appreciated that clinicians are faced with substantial challenges in managing blood pressure (BP) in persons with SCI, contrary to the prevailing belief, asymptomatic hypotension and OH are not benign conditions. Reports suggest that asymptomatic hypotensive individuals with SCI may have subclinical cognitive dysfunction affecting memory and attention processing and increased incidence of fatigue and depression compared to normotensive individuals with SCI. It must be appreciated that to date, there are no FDA approved pharmaceutical options proven to be safe and effective for treatment of hypotension and OH in the SCI population. Until 2014, midodrine hydrochloride was the only agent with FDA approval for treatment of symptomatic neurogenic OH (NOH). Midodrine, an alpha-agonist, is the most commonly prescribed agent used to treat symptomatic hypotension in the SCI population despite a lack of convincing evidence of safety or efficacy. In 2014 droxidopa (L-threo-3,4-dihydroxyphenylserine - NORTHERA; Chelsea Therapeutics, Charlotte, NC) was approved by the FDA for treatment of symptomatic NOH based on data collected in conditions of autonomic dysfunction. Droxidopa is a NE precursor that is stored in neuronal and non-neuronal tissue and has been shown to increase standing BP and reduce symptoms of orthostatic intolerance in individuals with symptomatic NOH. We recently reported preliminary evidence of a mean increase in seated BP in individuals with SCI following oral administration of 400 mg of droxidopa; however, this dose was effective in only 5 of the 10 subjects tested and the BP effect waned over a 4-hour observation. Because of its unique pharmacokinetic profile, droxidopa is a highly promising agent to treat hypotension in persons with SCI. As such; there exists a pressing imperative to determine the clinical value and safety of droxidopa in hypotensive individuals with SCI.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Study 1: Dose Optimization of Northera	Experimental	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours.	Drug: Northera
Study 2: Blinded Placebo & Northera	Placebo Comparator	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).	Drug: Northera Other: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Northera	Drug	Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.	Study 1: Dose Optimization of Northera Study 2: Blinded Placebo & Northera

Measure	Description	Time Frame
Proportion of Systolic BP Within a Normotensive Range	To determine the proportion (%) of normotensive systolic blood pressure for males=(110-120 mmHg); and females=(101-120 mmHg) following administration of droxidopa.	up to 240 minutes following administration of droxidopa

Measure	Description	Time Frame
Supine Systolic Blood Pressure	To measure supine systolic blood pressure following administration of droxidopa compared to placebo in hypotensive participants with SCI	within 60 minutes of administration of droxidopa or placebo
Orthostatic Systolic Blood Pressure

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Study 1:

Male or Female, age 18 to 89 with traumatic SCI.
SCI Subjects (n=40):
1. Any level of injury;
2. Any American Spinal Injury Association Impairment Scale (AIS) grade of SCI;
3. Non-ventilator dependent
4. Primarily wheelchair dependent for mobility;
5. Duration of injury < 1 year
Low Blood Pressure:
1. Systolic BP less than 110 mmHg and/or diastolic BP less than 70 mmHg for males.
2. Systolic BP less than 100 mmHg and/or diastolic BP less than 70 mmHg for females.
Primary Language is English.
Able to provide informed consent

Study 2:
Male or Female, age 18 to 89 with traumatic SCI.
SCI Subjects (n=40):
1. Any level of injury;
2. Any AIS grade of SCI;
3. Non-ventilator dependent
4. Primarily wheelchair dependent for mobility
5. Duration of injury < 1 year
Low Blood Pressure:
1. Systolic BP less than 110 mmHg and/or diastolic BP less than 70 mmHg for males.
2. Systolic BP less than 100 mmHg and/or diastolic BP less than 70 mmHg for females.
Primary Language is English.
Able to provide informed consent
Showed a normotensive blood pressure in response to Droxidopa during study 1.

Exclusion Criteria:

Current illness or infection
Individuals with frequent or severe autonomic dysreflexia:
1. More than 3 symptomatic events per week
2. BP ≥140/90 mmHg
3. Significant adverse subjective symptoms reporting
Hypertension
Any neurological condition other than SCI (Alzheimer's disease, dementia, stroke, multiple sclerosis, Parkinson's disease, etc.)
History of epilepsy or other seizure disorder
History of traumatic brain injury (TBI)
Liver or kidney disease
Bladder problems including blockage of the urine and/or weak urine stream.
Diagnosis of a psychiatric disorder such as schizophrenia or bipolar disorder
Known artery disease, heart failure, Atrio-ventricular block, and irregular heartbeat
Any allergies to droxidopa, asprin, polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide
Major surgery in the last 30 days
Illicit drug abuse in the past 6 months
Pregnant
Your prescription medications will be reviewed by the study investigators and research staff. If you are currently taking medications to treat any of the following please make the investigators aware:

d. Depression, Schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD) e. Pain (opioids) f. Infection or illness (antibiotics) g. Erectile dysfunction (Viagra, Cialis, etc.) h. Overactive bladder i. High or low blood pressure j. Migraine headaches k. Malaria l. asthma

Name	Affiliation	Role
Jill M Wecht, Ed.D	James J. Peter's VAMC	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
The Icahn School of Medicine at Mount Sinai		New York	New York	10029	United States
James J. Peters Veteran's Affair Medical Center

PubMed Identifier	Type	Citation	Retractions
17184183	Background	Claydon VE, Krassioukov AV. Orthostatic hypotension and autonomic pathways after spinal cord injury. J Neurotrauma. 2006 Dec;23(12):1713-25. doi: 10.1089/neu.2006.23.1713.
14087938	Background	GUTTMANN L, MUNRO AF, ROBINSON R, WALSH JJ. EFFECT OF TILTING ON THE CARDIOVASCULAR RESPONSES AND PLASMA CATECHOLAMINE LEVELS IN SPINAL MAN. Paraplegia. 1963 May;1:4-18. doi: 10.1038/sc.1963.2. No abstract available.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Study 1: Dose Optimization of Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP_ICF	Yes	Yes	Yes	Study Protocol, Statistical Analysis Plan, and Informed Consent Form	Jul 14, 2020

Arm/Group Information

ID	Title	Description
BG000	Study 1: Dose Optimization of Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.
BG001	Study 2: Blinded Placebo/Northera	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv). Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg. Placebo: Study 2 is blinded placebo controlled trial using the individualized optimal dose of droxidopa determined by study 1.
BG002	Study 2: Blinded Northera/Placebo	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).
BG003	Total	Total of all reporting groups

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

Proportion of Systolic BP Within a Normotensive Range

To determine the proportion (%) of normotensive systolic blood pressure for males=(110-120 mmHg); and females=(101-120 mmHg) following administration of droxidopa.

Posted

Number

Systolic Blood Pressure Recordings

up to 240 minutes following administration of droxidopa

Systolic Blood Pressure Recordings

ID	Title	Description
OG000	Study 1: Dose Optimization of Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.
OG001	Study 2: Placebo	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).
OG002	Study 2: Northera	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).

Units	Counts
Participants	OG00015 OG0016 OG0026
Systolic Blood Pressure Recordings	OG000

Title

Denominators

Categories

Title	Measurements
	OG000167 OG001117 OG00289

Secondary

Supine Systolic Blood Pressure

To measure supine systolic blood pressure following administration of droxidopa compared to placebo in hypotensive participants with SCI

Posted

Mean

Standard Deviation

mmHg

within 60 minutes of administration of droxidopa or placebo

ID	Title	Description
OG000	Study 1: Dose Optimization Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.
OG001	Study 2: Placebo	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.

Secondary

Orthostatic Systolic Blood Pressure

To document systolic blood pressure responses to head-up tilt to 70 degrees following administration of droxidopa compared to placebo in hypotensive participants with SCI.

Participants did not undergo a 70 degree head-up tilt in Study 1 the dose optimization trial.

Posted

Mean

Standard Deviation

mmHg

60-90 minutes following administration of droxidopa or placebo

ID	Title	Description
OG000	Study 1: Dose Optimization Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.
OG001	Study 2: Placebo	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.

Secondary

Orthostatic Cerebral Blood Flow

To compare cerebral blood flow velocity in the middle cerebral artery following administration of placebo compared to administration of Northera (Droxidopa)

We did not assess middle cerebral artery cerebral blood flow velocity in Study 1 following administration of Northera

Posted

Mean

Standard Deviation

cm/sec

60-90 minutes following administration of droxidopa or placebo

ID	Title	Description
OG000	Study 1: Dose Optimization of Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.
OG001	Study 2: Placebo	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (At Risk)
EG000	Study 1: Dose Optimization of Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours. Northera: Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.	15	15	15
EG001	Study 2: Northera	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).	6	6	6
EG002	Study 2: Placebo	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).	6	6	6

ID	Term
D007024	Hypotension, Orthostatic
D007022	Hypotension
D013119	Spinal Cord Injuries

ID	Term
D054971	Orthostatic Intolerance
D054969	Primary Dysautonomias
D001342	Autonomic Nervous System Diseases
D009422	Nervous System Diseases
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D013118	Spinal Cord Diseases
D002493	Central Nervous System Diseases
D020196	Trauma, Nervous System
D014947	Wounds and Injuries

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