Phase 3 Clinical Effect Durability of TD-9855 for Treatin... | NCT03829657

NCT03829657

ID	Type	Description	Link
2018-003941-41	EudraCT Number

Status Module

Label	Type	Description	Intervention Names
ampreloxetine (Open Label (OL))	Experimental	Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.	Drug: ampreloxetine
ampreloxetine	Experimental	After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.	Drug: ampreloxetine
Placebo	Placebo Comparator	After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
ampreloxetine	Drug	Oral tablet, QD (Daily)	ampreloxetine ampreloxetine (Open Label (OL))

Measure	Description	Time Frame
Proportion of Participants With Treatment Failure at Week 6 of RW Treatment Period	Treatment failure was defined as proportion of participants who met the following criteria at Week 6 following randomization: Change (worsening) from baseline in Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA#1) score of 1.0 point and worsening of disease severity as assessed by a 1-point change in Patient Global Impression of Severity (PGI-S). OHSA Question #1 assessed dizziness, lightheadedness, feeling faint, or feeling like you might blackout. PGI-S assessed patient's impression of disease severity. Least squares mean here is the model-based proportion of participants with treatment failure using logistic regression.	6-week randomized withdrawal period (Week 16 to Week 22)

Eligibility Module

Eligibility Criteria

Inclusion Criteria (For 0169 Completers Group):

Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with ampreloxetine. Only subjects with OHSA#1 score of ≤7 will be eligible for randomization for the double-blind treatment period.
Subject has a minimum of 80% study medication compliance in Study 0169.

Inclusion Criteria (For De Novo Group):

Subject is male or female and at least 30 years old.
Subject must meet the diagnostic criteria of symptomatic nOH, as demonstrated by a sustained reduction in BP of ≥20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 min of being tilted-up ≥60o from a supine position as determined by a tilt-table test.
Subject must score at least a 4 on the OHSA#1 at V1.
For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria (1992).
For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
For subjects with PAF only: Subject has documented impaired autonomic reflexes, including the Valsalva maneuver performed within 24 months from the date of randomization
Subject has plasma Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated position for 30 minutes.

Exclusion Criteria (For 0169 Completers Group):

Subject has a medical, laboratory, or surgical issue(s) deemed by the investigator to be clinically significant.
Subject has an uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.

Exclusion Criteria (For De Novo Group):

Subject has a known systemic illness known to produce autonomic neuropathy, including but not limited to amyloidosis, and autoimmune neuropathies.
Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (SNRIs).
Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension unrelated to autonomic dysfunction.
Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to V1 or requires concomitant use until the follow-up visit.
Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to V1.
- Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1.
Subject has known or suspected alcohol or substance abuse within the past 12 months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse).
Subject has a clinically unstable coronary artery disease, or has had a major cardiovascular or neurological event in the past 6 months.
Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
Subject has any significant uncontrolled cardiac arrhythmia.
Subject has a Montreal Cognitive Assessment (MoCA) ≤23.
Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
Subject had a myocardial infarction in the past 6 months or has current unstable angina.
Subject has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
Subject has a clinically significant abnormal laboratory finding (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could interfere with safety of the subject).
Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the Columbia Suicide Severity Rating Scale (C-SSRS)(Baseline/Screening Version). Subject should be assessed by the rater for risk of suicide and the subject's appropriateness for inclusion in the study.

Name	Affiliation	Role
Medical Monitor	Theravance Biopharma	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Banner Sun Health Research Institute		Sun City	Arizona	85351	United States
UC San Diego Movement Disorder Center

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	OL Treatment Period: 0169 Placebo Rollover	Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.
FG001	OL Treatment Period: 0169 Ampreloxetine Rollover

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	Aug 5, 2020	Nov 7, 2022

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 Participants With Treatment Failure at Week 6 of RW Treatment Period

Treatment failure was defined as proportion of participants who met the following criteria at Week 6 following randomization: Change (worsening) from baseline in Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA#1) score of 1.0 point and worsening of disease severity as assessed by a 1-point change in Patient Global Impression of Severity (PGI-S). OHSA Question #1 assessed dizziness, lightheadedness, feeling faint, or feeling like you might blackout. PGI-S assessed patient's impression of disease severity.

Least squares mean here is the model-based proportion of participants with treatment failure using logistic regression.

RW Treatment Period Full Analysis Set: all randomized participants who received at least 1 dose of study medication (ampreloxetine or placebo) following randomization.

Posted

Least Squares Mean

Standard Error

Proportion of participants

6-week randomized withdrawal period (Week 16 to Week 22)

ID	Title	Description
OG000	RW Treatment Period: Placebo	Participants who completed the OL treatment period and were randomized to receive oral placebo QD for a further 6 weeks in the RW treatment period.
OG001	RW Treatment Period: Ampreloxetine	Participants who completed the OL treatment period and were randomized to receive 10 mg oral ampreloxetine QD for a further 6 weeks in the RW treatment period.

Units	Counts
Participants	OG00064 OG00164

Title

Denominators

Categories

Title	Measurements
	OG0000.42± 0.068 OG0010.30± 0.065

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		Regression, Logistic		0.196		Odds Ratio (OR)	0.60			2-Sided	95	0.27	1.29					Superiority

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	OL Treatment Period: 0169 Placebo Rollover	Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.	2	83	7	83	41	83
EG001	OL Treatment Period: 0169 Ampreloxetine Rollover	Participants who received ampreloxetine in study 0169, received 10 mg oral ampreloxetine QD for up to 16 weeks.	3	85	8	85	48	85
EG002	OL Treatment Period: De Novo	Participants with symptomatic neurogenic orthostatic hypotension (nOH) who met all applicable study inclusion criteria and none of the applicable exclusion criteria, received 10 mg oral ampreloxetine QD for up to 16 weeks. These participants did not roll over from the 0169 study.	0	32	1	32	16	32
EG003	RW Treatment Period: Placebo	Participants who completed the OL treatment period and were randomized to receive oral placebo QD for a further 6 weeks in the RW treatment period.	0	64	2	64	16	64
EG004	RW Treatment Period: Ampreloxetine	Participants who completed the OL treatment period and were randomized to receive 10 mg oral ampreloxetine QD for a further 6 weeks in the RW treatment period.	2	64	4	64	17	64

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Urinary tract infection	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG0031 affected64 at risk EG0040 affected64 at risk
COVID-19	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Pneumonia	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Pneumonia aspiration	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Bulbar palsy	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Loss of consciousness	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Neurological decompensation	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Parkinson's disease	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hip fracture	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Femur fracture	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Injury	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Atrial flutter	Cardiac disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Atrioventricular block	Cardiac disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Bradycardia	Cardiac disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Myocardial infarction	Cardiac disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Diarrhoea	Gastrointestinal disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Enterocolitis	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Death	General disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Subcapsular renal haematoma	Renal and urinary disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hip arthroplasty	Surgical and medical procedures	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Orthostatic hypotension	Vascular disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Respiratory tract infection	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Spinal column injury	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Urinary tract infection	Infections and infestations	24.1	Systematic Assessment	EG0002 affected83 at risk EG0018 affected85 at risk EG0022 affected32 at risk EG0033 affected64 at risk EG0042 affected64 at risk
Headache	Nervous system disorders	24.1	Systematic Assessment	EG0005 affected83 at risk EG0013 affected85 at risk EG0020 affected32 at risk EG003
Dizziness	Nervous system disorders	24.1	Systematic Assessment	EG0004 affected83 at risk EG0013 affected85 at risk EG0020 affected32 at risk EG003
Nausea	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0015 affected85 at risk EG0022 affected32 at risk EG003
Syncope	Nervous system disorders	24.1	Systematic Assessment	EG0002 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Loss of consciousness	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Memory impairment	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
On and off phenomenon	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Balance disorder	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Burning sensation	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Dizziness exertional	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Dizziness postural	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Dyskinesia	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Hypokinesia	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Multiple system atrophy	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Oromandibular dystonia	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Presyncope	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Radial nerve palsy	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Restless legs syndrome	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Somnolence	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Spasmodic dysphonia	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Speech disorder	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Tremor	Nervous system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
COVID-19	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Nasopharyngitis	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0021 affected32 at risk EG003
Conjunctivitis	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Oral candidiasis	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Pharyngitis streptococcal	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Rhinitis	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Tooth abscess	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Urinary tract infection bacterial	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Viral upper respiratory tract infection	Infections and infestations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Constipation	Gastrointestinal disorders	24.1	Systematic Assessment	EG0002 affected83 at risk EG0014 affected85 at risk EG0020 affected32 at risk EG003
Diarrhoea	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Dry mouth	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0021 affected32 at risk EG003
Flatulence	Gastrointestinal disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Inguinal hernia	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Retching	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Toothache	Gastrointestinal disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Vomiting	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Anxiety	Psychiatric disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0013 affected85 at risk EG0020 affected32 at risk EG003
Depression	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Insomnia	Psychiatric disorders	24.1	Systematic Assessment	EG0002 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Hallucination	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Agitation	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Bruxism	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Confusional state	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hallucination, visual	Psychiatric disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hypomania	Psychiatric disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Mental status changes	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Panic attack	Psychiatric disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Sleep disorder	Psychiatric disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0013 affected85 at risk EG0020 affected32 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Rash	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0021 affected32 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hair growth rate abnormal	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hand dermatitis	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Palmar erythema	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Rash pruritic	Skin and subcutaneous tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Oedema peripheral	General disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Pyrexia	General disorders	24.1	Systematic Assessment	EG0003 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Fatigue	General disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Chest pain	General disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Discomfort	General disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Gait disturbance	General disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Malaise	General disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Pain	General disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Peripheral swelling	General disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Contusion	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0021 affected32 at risk EG003
Fall	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0022 affected32 at risk EG003
Arthropod bite	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hand fracture	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Skin laceration	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Blood creatine phosphokinase increased	Investigations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Blood creatinine increased	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Blood lactate dehydrogenase increased	Investigations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Blood pressure increased	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Blood urea increased	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Colonoscopy	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Glomerular filtration rate abnormal	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Glomerular filtration rate decreased	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Haematocrit decreased	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Platelet count decreased	Investigations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Troponin increased	Investigations	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0021 affected32 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0021 affected32 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Groin pain	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Joint swelling	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Osteoporosis	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Tendonitis	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Orthostatic hypotension	Vascular disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hypertension	Vascular disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Flushing	Vascular disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hot flush	Vascular disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Supine hypertension	Vascular disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
White coat hypertension	Vascular disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	24.1	Systematic Assessment	EG0002 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Vision blurred	Eye disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Conjunctival haemorrhage	Eye disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Diplopia	Eye disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Hypermetropia	Eye disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Open angle glaucoma	Eye disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Vitreous floaters	Eye disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Calculus urinary	Renal and urinary disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Haematuria	Renal and urinary disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Nocturia	Renal and urinary disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Pollakiuria	Renal and urinary disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Urinary hesitation	Renal and urinary disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Urinary retention	Renal and urinary disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Anaemia	Blood and lymphatic system disorders	24.1	Systematic Assessment	EG0002 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Atrioventricular block first degree	Cardiac disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Bundle branch block left	Cardiac disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Tachycardia	Cardiac disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0012 affected85 at risk EG0020 affected32 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Vitamin D deficiency	Metabolism and nutrition disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Allergy to vaccine	Immune system disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Seasonal allergy	Immune system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Gynaecomastia	Reproductive system and breast disorders	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Priapism	Reproductive system and breast disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Cholecystitis chronic	Hepatobiliary disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Haemangioma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0021 affected32 at risk EG003
Device occlusion	Product Issues	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003
Walking disability	Social circumstances	24.1	Systematic Assessment	EG0001 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Bronchitis	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Upper respiratory tract infection	Infections and infestations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Migraine with aura	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Parkinson's disease	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Radiculopathy	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Asthenia	General disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hyperthermia	General disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Back injury	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Limb injury	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Post procedural discomfort	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Soft tissue injury	Injury, poisoning and procedural complications	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Large intestine polyp	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Mobility decreased	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Diastolic hypertension	Vascular disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Hypotension	Vascular disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Calculus bladder	Renal and urinary disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Anaemia vitamin B12 deficiency	Blood and lymphatic system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Myocardial infarction	Cardiac disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Cystoscopy	Investigations	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Endometrial hyperplasia	Reproductive system and breast disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Ovarian cyst	Reproductive system and breast disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Uterine enlargement	Reproductive system and breast disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0010 affected85 at risk EG0020 affected32 at risk EG003
Bulbar palsy	Nervous system disorders	24.1	Systematic Assessment	EG0000 affected83 at risk EG0011 affected85 at risk EG0020 affected32 at risk EG003

ID	Term
D010300	Parkinson Disease
D054970	Pure Autonomic Failure
D007024	Hypotension, Orthostatic
D007022	Hypotension
D004244	Dizziness
D013575	Syncope
D020734	Parkinsonian Disorders

ID	Term
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
D054971	Orthostatic Intolerance
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D012678	Sensation Disorders
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D014474	Unconsciousness
D003244	Consciousness Disorders
D019954	Neurobehavioral Manifestations

ID	Title	Description
BG000	OL Treatment Period: 0169 Placebo Rollover	Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.
BG001	OL Treatment Period: 0169 Ampreloxetine Rollover	Participants who received ampreloxetine in study 0169, received 10 mg oral ampreloxetine QD for up to 16 weeks.
BG002	OL Treatment Period: De Novo	Participants with symptomatic neurogenic orthostatic hypotension (nOH) who met all applicable study inclusion criteria and none of the applicable exclusion criteria, received 10 mg oral ampreloxetine QD for up to 16 weeks. These participants did not roll over from the 0169 study.
BG003	Total	Total of all reporting groups