Sustained Effect of Droxidopa in Symptomatic Neurogenic O... | NCT02586623

ID	Type	Description	Link
NOH402	Other Identifier	NOH402

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Open Label Period	Experimental	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open Label Titration Period, patients will first receive 100 mg TID and their dose will be raised (in 100 mg increments) at subsequent visits until optimal dose is determined. During the Open Label Treatment Period, patients will receive active droxidopa100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to the patient's individual dose at the end of the Open-Label Titration Period).	Drug: Droxidopa capsules
Randomized Period	Placebo Comparator	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to patients individual dose at the end of the Open-Label Period) or matching placebo.	Drug: Droxidopa capsules Drug: Placebo capsules

Name	Type	Description	Arm Group Labels	Other Names
Droxidopa capsules	Drug	100, 200 or 300 mg	Open Label Period Randomized Period

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Time To Intervention	Kaplan-Meier estimates are presented for time to treatment intervention. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to need for treatment intervention. Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period: OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR participant stops IMP or withdraws from study for patient-reported lack of efficacy.	Randomization (Day 0) up to Week 12

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants Who Needed Intervention During the 12-week Double-Blind Treatment Period	Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period: OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR participant stops IMP or withdraws from study for patient-reported lack of efficacy.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

18 years or older and able to stand (with or without limited assistance)
Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary Autonomic Failure (PD, MSA or PAF) or NDAN or DBH Deficiency
Score of at least 4 or greater on Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 (measured at Screening [Visit 1] and the first Titration Visit [Visit 2a] prior to dosing)
A documented drop of at least 20 millimeters of mercury (mmHg) in SBP, within 3 minutes of standing. This can either be documented in the patient history or assessed during Screening prior to the first Titration Visit (Visit 2a)
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

Additional inclusion criteria for patients taking prescribed droxidopa prior to study entry:

Patients who are taking prescribed droxidopa therapy are eligible to participate in the study if they meet the other inclusion criteria and also have been on a stable dose of prescribed droxidopa for at least 2 weeks prior to the Screening Visit (Visit 1). In addition, they must meet either of the following at the Screening Visit (Visit 1):

The patient's Visit 1 OHSA Item #1 score is ≥ 7 AND the prescribed dose is ≤ 300 mg three times daily (TID); OR
The patient's Visit 1 OHSA Item #1 score is ≤6 AND worsens by ≥ 2 units when retested after washing out of droxidopa for at least 3 days

Exclusion Criteria:

In the investigator's opinion, the patient is not able to understand or cooperate with study procedures
Known or suspected alcohol or substance use disorder within the past 12 months (DSM-5 criteria)
Women who are pregnant or breastfeeding
Women of childbearing potential (WOCP) who are not using at least one method of contraception with their partner
Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic. Sustained is defined as the average of 3 observations each at least 10 minutes apart with the patient having been supine and at rest for at least 5 minutes prior to each measurement.
Untreated closed angle glaucoma
Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study)
Any significant uncontrolled cardiac arrhythmia
History of myocardial infarction or stroke, within the past 2 years
Current unstable angina
Congestive heart failure (NYHA Class 3 or 4)
Diabetic autonomic neuropathy
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
Any major surgical procedure within the past 30 days
Currently receiving any investigational drug or have received an investigational drug within the past 28 days

Additional protocol defined exclusion criteria do apply

Name	Affiliation	Role
Email contact via H. Lundbeck A/S	LundbeckClinicalTrials@Lundbeck.com	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
MDFirst Research - Chandler		Chandler	Arizona	85226	United States
21st Century Neurology

PubMed Identifier	Type	Citation	Retractions
35107750	Derived	Hauser RA, Favit A, Hewitt LA, Lindsten A, Gorny S, Kymes S, Isaacson SH. Durability of the Clinical Benefit of Droxidopa for Neurogenic Orthostatic Hypotension During 12 Weeks of Open-Label Treatment. Neurol Ther. 2022 Mar;11(1):459-469. doi: 10.1007/s40120-021-00317-5. Epub 2022 Feb 2.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Open-Label Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open-Label period, participants received 100 mg TID and their dose was raised (in 100 mg TID increments) at subsequent visits until optimal dose was determined. Participants then received active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to the participant's individual optimal dose).

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	Yes	No	No	Study Protocol	Mar 18, 2021	Jul 20, 2023

Arm/Group Information

ID	Title	Description
BG000	Open-Label Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open-Label period, participants received 100 mg TID and their dose was raised (in 100 mg TID increments) at subsequent visits until optimal dose was determined. Participants then received active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to the participant's individual optimal dose).
BG001	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
BG002	Double-Blind Placebo	Matching placebo for droxidopa TID orally
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Data are being reported separately for the open-label and double-blind periods.

Mean

Standard Deviation

years

Title	Denominators	Categories
Open-Label Period	ParticipantsBG000451 ParticipantsBG0010 ParticipantsBG0020 ParticipantsBG003

Sex: Female, Male

Data are being reported separately for the open-label and double-blind periods.

Count of Participants

Participants

Title	Denominators	Categories
Open-Label Period	ParticipantsBG000451 ParticipantsBG0010 ParticipantsBG002

Ethnicity (NIH/OMB)

Data are being reported separately for the open-label and double-blind periods.

Count of Participants

Participants

Title	Denominators	Categories
Open-Label Period	ParticipantsBG000451 ParticipantsBG0010 ParticipantsBG002

Race (NIH/OMB)

Data are being reported separately for the open-label and double-blind periods.

Count of Participants

Participants

Title	Denominators	Categories
Open-Label Period	ParticipantsBG000451 ParticipantsBG0010 ParticipantsBG002

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

Time To Intervention

Kaplan-Meier estimates are presented for time to treatment intervention. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to need for treatment intervention.

Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period:

OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR
participant stops IMP or withdraws from study for patient-reported lack of efficacy.

The Full-analysis Set (FAS) included all randomized participants who took at least one dose of IMP in the Double-Blind Treatment Period.

Posted

Number

95% Confidence Interval

Days

Randomization (Day 0) up to Week 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo	Matching placebo for droxidopa TID orally

Units	Counts
Participants	OG000126 OG001126

Title

Denominators

Categories

25%

Title	Measurements
	OG00052.00(26.00 to 72.00) OG00142.00(27.00 to 86.00)

50%

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Log Rank		0.803		Cox Proportional Hazard	1.04			2-Sided	95	0.67	1.62			Droxidopa / Placebo		Superiority

Secondary

Number of Participants Who Needed Intervention During the 12-week Double-Blind Treatment Period

Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period:

OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR
participant stops IMP or withdraws from study for patient-reported lack of efficacy.

The FAS included all randomized participants who took at least one dose of IMP in the Double-Blind Treatment Period.

Posted

Count of Participants

Participants

Randomization (Day 0) up to Week 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo	Matching placebo for droxidopa TID orally

Units	Counts
Participants

Secondary

Time To All-cause Discontinuation

Kaplan-Meier estimates are presented for time to all-cause discontinuation. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to discontinuation. Time to all-cause discontinuation was defined as the time from randomization to withdrawal or last contact date.

The FAS included all randomized participants who took at least one dose of IMP in the Double-Blind Treatment Period.

Posted

Number

95% Confidence Interval

Days

Randomization (Day 0) up to Week 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo	Matching placebo for droxidopa TID orally

Units	Counts
Participants	OG000

Secondary

Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 Score

The OHSA scale was designed to rate symptoms occurring specifically as a result of low blood pressure (BP), on average, over the past week using an 11-point scale (0 to 10), with more severe symptoms scoring higher. A score of zero indicates that the symptom was not experienced, and 10 is the worst possible. The scale was used to assess six symptoms: 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. Scores for each activity and a composite score for all six activities were tabulated. A mean negative change from baseline means that symptoms have improved. A mean positive change from baseline means that symptoms have gotten worse.

The FAS included all randomized participants who took at least one dose of IMP in the Double-Blind Treatment Period. Here, 'Overall number of subjects analyzed' signifies participants evaluable for this outcome measure and "Number analyzed" is the number of participants evaluated at each time point.

Posted

Mean

Standard Deviation

Score on a scale

Randomization (Day 0); Weeks 2 to 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo

Secondary

Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Questionnaire (OHQ) Composite Score

The OHQ composite score was a mean of the OHSA composite and the Orthostatic Hypotension Daily Activity Scale (OHDAS) composite scores. The OHDAS was designed as a measure of quality of life. It uses an 11-point scale to assess whether orthostatic hypotension (OH) "interfered" with four types of activities: 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. A zero rating means that over the preceding week the activity was performed with no interference and a 10 rating means that orthostatic hypotension completely interfered with the activity. Scores for each activity and a composite score for all four activities were tabulated. A mean negative change from baseline means that symptoms have improved. A mean positive change from baseline means that symptoms have gotten worse.

Posted

Mean

Standard Deviation

Score on a scale

Randomization (Day 0); Weeks 2 to 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo

Secondary

Clinician-rated Clinical Global Impressions - Severity (CGI-S)

The CGI-S was developed to provide global measures of the severity of a participant's clinical condition during clinical studies. The CGI-S was utilized by both the clinician and the participant to provide an impression of the participant's current state of OH. The severity of the participant's current illness was rated by the clinician on a 7-point scale ranging from 1 (normal, no OH) to 7 (among those patients most extremely ill with OH).

Posted

Mean

Standard Deviation

Score on a scale

Weeks 2 to 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo	Matching placebo for droxidopa TID orally

Units	Counts

Secondary

Participant-rated CGI-S

The CGI-S was developed to provide global measures of the severity of a participant's clinical condition during clinical studies. The CGI-S was utilized by both the clinician and the participant to provide an impression of the participant's current state of OH. The severity of the participant's current illness was rated by the participant on a 7-point scale ranging from 1 (normal, no OH) to 7 (most extremely ill with OH).

Posted

Mean

Standard Deviation

Score on a scale

Weeks 2 to 12

ID	Title	Description
OG000	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)
OG001	Double-Blind Placebo	Matching placebo for droxidopa TID orally

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Open-Label Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open-Label period, participants received 100 mg TID and their dose was raised (in 100 mg TID increments) at subsequent visits until optimal dose was determined. Participants then received active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to the participant's individual optimal dose).	6	451	45	451	192	451
EG001	Double-Blind Droxidopa	Active droxidopa 100, 200, 300, 400, 500, or 600 mg TID orally (equal to participant's individual dose at the end of the Open-Label Period)	1	126	3	126	32	126
EG002	Double-Blind Placebo	Matching placebo for droxidopa TID orally	0	126	8	126	22	126

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Iron deficiency anaemia	Blood and lymphatic system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Leukocytosis	Blood and lymphatic system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Angina pectoris	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Arrhythmia	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Bradycardia	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Cardiac arrest	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0011 events1 affected126 at risk EG0020 events0 affected126 at risk
Cardiac failure acute	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Myocarditis	Cardiac disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Colitis ischaemic	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0011 events1 affected126 at risk EG0020 events0 affected126 at risk
Dysphagia	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Inguinal hernia	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Retroperitoneal haemorrhage	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Pyrexia	General disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Biliary dyskinesia	Hepatobiliary disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Pneumonia	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0022 events2 affected126 at risk
Pneumonia aspiration	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0004 events3 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Pneumonia staphylococcal	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Pyelonephritis acute	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Sepsis	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Urinary tract infection bacterial	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Urinary tract infection pseudomonal	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Urosepsis	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Viral infection	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Acetabulum fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Face injury	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0006 events6 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Fibula fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Head injury	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Hip fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Tibia fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Failure to thrive	Metabolism and nutrition disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Spinal stenosis	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Brain stem infarction	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Cerebellar infarction	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0003 events3 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Depressed level of consciousness	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Dizziness	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Encephalopathy	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Hypersomnia	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Hypertensive encephalopathy	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Presyncope	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Seizure like phenomena	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Syncope	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0005 events4 affected451 at risk EG0011 events1 affected126 at risk EG0023 events3 affected126 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Agitation	Psychiatric disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Alcohol abuse	Psychiatric disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Delusion	Psychiatric disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Hallucination	Psychiatric disorders	MedDRA 25.0	Non-systematic Assessment	EG0000 events0 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Renal tubular necrosis	Renal and urinary disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Urinary tract obstruction	Renal and urinary disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Idiopathic pulmonary fibrosis	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Lung opacity	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Stridor	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Decubitus ulcer	Skin and subcutaneous tissue disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Hypertension	Vascular disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Hypertensive urgency	Vascular disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk
Orthostatic hypotension	Vascular disorders	MedDRA 25.0	Non-systematic Assessment	EG0002 events2 affected451 at risk EG0010 events0 affected126 at risk EG0021 events1 affected126 at risk
Shock haemorrhagic	Vascular disorders	MedDRA 25.0	Non-systematic Assessment	EG0001 events1 affected451 at risk EG0010 events0 affected126 at risk EG0020 events0 affected126 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA 25.0	Non-systematic Assessment	EG00054 events43 affected451 at risk EG0011 events1 affected126 at risk EG0021 events1 affected126 at risk
Fatigue	General disorders	MedDRA 25.0	Non-systematic Assessment	EG00027 events24 affected451 at risk EG0013 events3 affected126 at risk EG0021 events1 affected126 at risk
Urinary tract infection	Infections and infestations	MedDRA 25.0	Non-systematic Assessment	EG00030 events26 affected451 at risk EG00111 events10 affected126 at risk EG0025 events5 affected126 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 25.0	Non-systematic Assessment	EG00083 events49 affected451 at risk EG00110 events8 affected126 at risk EG0029 events5 affected126 at risk
Dizziness	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG00049 events39 affected451 at risk EG0018 events7 affected126 at risk EG0027 events5 affected126 at risk
Headache	Nervous system disorders	MedDRA 25.0	Non-systematic Assessment	EG00090 events69 affected451 at risk EG0014 events4 affected126 at risk EG0028 events7 affected126 at risk
Hypertension	Vascular disorders	MedDRA 25.0	Non-systematic Assessment	EG00027 events24 affected451 at risk EG0011 events1 affected126 at risk EG0024 events3 affected126 at risk

ID	Term
D010300	Parkinson Disease
D019578	Multiple System Atrophy
D054970	Pure Autonomic Failure
C535600	dopamine beta hydroxylase deficiency

ID	Term
D020734	Parkinsonian Disorders
D001480	Basal Ganglia Diseases
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D009069	Movement Disorders
D000080874	Synucleinopathies
D019636	Neurodegenerative Diseases
D054969	Primary Dysautonomias
D001342	Autonomic Nervous System Diseases

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