Clinical Trials Register

Summary
EudraCT Number:	2018-003289-15
Sponsor's Protocol Code Number:	0169
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-07-24
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2018-003289-15

A.3

Full title of the trial

A Phase 3, 4-week, Multicenter, Randomized, Double-blind,
Placebo-controlled, Parallel-group Study of TD-9855 in
Treating Symptomatic Neurogenic Orthostatic Hypotension in
Subjects With Primary Autonomic Failure

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

This study will look at whether an investigational drug called TD-9855 works and how safe it is for treating symptomatic neurogenic orthostatic hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA) or pure autonomic failure (PAF)

A.3.2

Name or abbreviated title of the trial where available

Sequoia study

A.4.1

Sponsor's protocol code number

0169

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Theravance Biopharma Ireland Limited
B.1.3.4	Country	Ireland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Theravance Biopharma Ireland Limited
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Theravance Biopharma Ireland Limited
B.5.2	Functional name of contact point	Brett Haumann
B.5.3	Address:
B.5.3.1	Street Address	Connaught House, 1 Burlington Road
B.5.3.2	Town/ city	Dublin 4
B.5.3.3	Post code	D04 C5Y6
B.5.3.4	Country	Ireland
B.5.4	Telephone number	0035315394800
B.5.6	E-mail	bhaumann@theravance.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	TD-9855
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ampreloxetine hydrochloride
D.3.9.1	CAS number	1227056-84-9
D.3.9.2	Current sponsor code	TD-9855
D.3.9.4	EV Substance Code	SUB194904
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

E.1.1.1

Medical condition in easily understood language

symptomatic neurogenic Orthostatic Hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA) or pure autonomic failure (PAF)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of TD-9855 in subjects with multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) experiencing symptomatic neurogenic orthostatic hypotension (syptomatic nOH) compared with placebo at Week 4, as measured by the change from baseline of the Orthostatic Hypotension Symptom Assessment (OHSA) Question 1 (OHSA#1) score.

E.2.2

Secondary objectives of the trial

− To evaluate the efficacy of TD-9855 by symptom and activity
assessments using OHSA and the Orthostatic Hypotension Daily
Activities Scale (OHDAS).
− To evaluate the efficacy of TD-9855 using the Patient Global
Impression of Change (PGI-C).
− To evaluate the efficacy of TD-9855 in preventing incidence of falls.
− To evaluate the safety and tolerability of TD-9855, including adverse
events (AEs) and changes in blood pressure (BP), heart rate (HR),
electrocardiogram (ECG), Columbia Suicide Severity Rating Scale (CSSRS)
and laboratory tests.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:
A subject who meets the following criteria will be eligible for study enrollment:
1. Subject is male or female and at least 30 years old.

2. Subject is female and must be nonpregnant and nonlactating. A woman of childbearing potential must have a documented negative pregnancy test at screening.
NOTE: A woman is considered to be of childbearing potential unless she is postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile (bilateral tubal ligation or total hysterectomy). A female subject may be admitted to the study on the basis of a negative urine pregnancy test. If the urine bHCG (beta human chorionic gonadotropin) test is positive, a serum bHCG test must be performed. The pregnancy test must be confirmed negative for a subject to be eligible for this study.

3. During the study and for 30 days after receiving the last dose of the study drug, females of childbearing potential or males capable of fathering children must agree to use highly effective birth control measures (failure rate <1% when used consistently and correctly) or agree to abstain from sexual intercourse (Refer to Section 4.3).

4. Subject must meet the diagnostic criteria of nOH, as demonstrated by a sustained reduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg
(diastolic) within 3 minutes of being tilted-up to ≥60 degrees from a
supine position as determined by a tilt-table test.

5. Subject must score at least a 4 on the Orthostatic Hypotension
Symptom Assessment Question #1 at randomization visit.

6. 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).

7. 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).

8. For subjects with PAF only: Subject has documented impaired
autonomic reflexes, including the Valsalva maneuver performed within
24 months from the date of randomization.

9. Subject has plasma NE levels >100 pg/mL after being in seated
position for 30 minutes.

10. Subject is willing and able to provide signed and dated written
informed consent to participate prior to initiation of any study related
procedures.

11. Subject is able to communicate well with the Investigator and clinic
staff, understands the expectations of the study and is able to comply
with the study procedures, requirements, and restrictions.

E.4

Principal exclusion criteria

1. Subject has a known systemic illness known to produce autonomic
neuropathy, including but not limited to amyloidosis and autoimmune
neuropathies. Subject has diabetes mellitus and diagnosis of PAF.
Subject with diabetes mellitus and either MSA or PD, will be evaluated
on a case by case basis by the medical monitor and considered ineligible
unless they meet all of the following criteria:
a. Well controlled type-2 DM in treatment with only oral medications and
diet
b. HgbA1C of ≤7.5% performed during screening or up to 12 weeks
before screening
c. No clinically evident peripheral neuropathy (e.g., normal sensory
examination on peripheral extremities)
d. No known retinopathy (e.g., annual ophthalmic exam is sufficient)
e. No nephropathy (e.g., absence of albuminuria and GFR >60)

2. Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (SNRIs).

3. Subject currently uses concomitant antihypertensive medication for the
treatment of essential hypertension.

4. Subject has used strong CYP1A2 inhibitors or inducers within 7 days or
5 half-lives, whichever is longer, prior to randomization or requires
concomitant use until the follow-up visit.

5. Subject has changed dose, frequency, or type of prescribed medication
for orthostatic hypotension within 7 days prior to randomization visit.
Midodrine and droxidopa (if applicable) must be tapered off at least 7
days prior to randomization.

6. Subject has a known or suspected alcohol or substance abuse within the past 12 months (DSM-IV-TR® definition of alcohol or substance abuse).

7. Subject has a clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months.

8. Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to randomization.

9. 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.

10. Subject has any significant uncontrolled cardiac arrhythmia.

11. Subject has a Montreal Cognitive Assessment (MoCA) ≤23.

12. Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.

13. Subject had a myocardial infarction in the past 6 months or has current unstable angina.

14. Subject has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).

15. Subject has any malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma within the past 2 years prior to screening.

16. Subject has a known gastrointestinal (GI) condition, which in the investigator’s judgment, may affect the absorption of study medication (e.g., ulcerative colitis, gastric bypass).

17. Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of the subject to give informed consent or interfere with the conduct of the study.

18. Subject is currently receiving any investigational drug or has received an investigational drug within 30 days of dosing. An investigational drug is defined as nonregulatory agency approved drug (e.g., Food and Drug Administration).

19. Subject has a clinically significant abnormal laboratory findings (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/1.73m2, or any abnormal laboratory value that could interfere with safety of the subject).

20. Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the 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.

21. 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.

22. Subject has known hypersensitivity to TD-9855 (ampreloxetine hydrochloride), or any excipients in the formulation.

23. Subject has (i) confirmed severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) documented with coronavirus disease 2019 [COVID-19] positive test result, OR (ii) is suspected of SARS-CoV-2 infection (clinical features without documented test results two weeks after resolution of symptoms and remains asymptomatic until Day 1), OR (iii) has been in close contact with a person with known (or suspected) SARS-CoV-2 infection and remains asymptomatic until Day 1.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in OHSA#1 (dizziness, lightheadedness, feeling faint, or feeling like blacking out) at Week 4.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 4.

E.5.2

Secondary end point(s)

• Change from baseline in OHSA composite score in Weeks 1 to 4
• Change from baseline in OHDAS composite score in Weeks 1 to 4
• PGI-C at Week 4
• Incidence of falls

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 4.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Austria

Bulgaria

Canada

Chile

Denmark

Estonia

France

Germany

Hungary

Israel

Italy

Mexico

New Zealand

Peru

Poland

Portugal

Russian Federation

Spain

Ukraine

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of trial is LPLV for those who choose not to continue in Study 170.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

188

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects completing the 4-week double-blind treatment period will be eligible to enroll and continue receiving study medication in Study 0170.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-07-21

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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