REDWOOD: Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure

Sponsor

Theravance Biopharma (Industry)

Overall Status

Terminated

CT.gov ID

NCT03829657

Collaborator

(none)

203

Enrollment

Locations

Arms

32.6

Actual Duration (Months)

2.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

Condition or Disease	Intervention/Treatment	Phase
Symptomatic Neurogenic Orthostatic Hypotension MSA Parkinson's Disease (PD) Pure Autonomic Failure (PAF)	Drug: ampreloxetine Drug: Placebo	Phase 3

Detailed Description

Phase 3, multi-center, randomized withdrawal study to evaluate the sustained benefit in efficacy and safety of ampreloxetine in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH. The study consists of 3 periods: (i) 16-week open-label (OL) treatment with ampreloxetine, (ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up (only for patients who do not enroll in Study 0171 (long-term extension safety study)).

Study Design

Study Type:

Interventional

Actual Enrollment :

203 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open Label Extension followed by Randomized Parallel AssignmentOpen Label Extension followed by Randomized Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure

Actual Study Start Date :

Feb 22, 2019

Actual Primary Completion Date :

Nov 10, 2021

Actual Study Completion Date :

Nov 10, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ampreloxetine (Open Label (OL)) Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.	Drug: ampreloxetine Oral tablet, QD (Daily) Other Names: TD-9855
Experimental: ampreloxetine After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.	Drug: ampreloxetine Oral tablet, QD (Daily) Other Names: TD-9855
Placebo Comparator: Placebo After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.	Drug: Placebo Oral tablet, QD

Arm

Intervention/Treatment

Experimental: ampreloxetine (Open Label (OL))

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.

Drug: ampreloxetine

Oral tablet, QD (Daily)

Other Names:

TD-9855

Experimental: ampreloxetine

After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.

Drug: ampreloxetine

Oral tablet, QD (Daily)

Other Names:

TD-9855

Placebo Comparator: Placebo

After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.

Drug: Placebo

Oral tablet, QD

Outcome Measures

Primary Outcome Measures

Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening of disease severity as assessed by a 1 point change in PGI-S [6-week randomized withdrawal period (Week 16 to Week 22)]
Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout and Score change from baseline on Patient Global Impression of Severity (PGI-S). PGI-S assesses patient's impression of disease severity.

Secondary Outcome Measures

Change from baseline in OHSA#1 at Week 6 post randomization at Week 6 post randomization. [6-week randomized withdrawal period (Week 16 to Week 22)]
Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout.
Change from baseline in OHSA composite score at Week 6 post randomization [6-week randomized withdrawal period (Week 16 to Week 22)]
Orthostatic Hypotension Symptom Assessment (OHSA) is an assessment of the severity of symptoms from low blood pressure.
Change from baseline in OHDAS composite score at Week 6 post randomization [6-week randomized withdrawal period (Week 16 to Week 22)]
Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life. OHDAS is a 4 item assessment that uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.
Change from baseline in PGI-S at Week 6 post randomization [6-week randomized withdrawal period (Week 16 to Week 22)]
Score change from baseline on Patient Global Impression of Severity (PGI-S). PGI-S assesses patient's impression of disease severity.
Change from baseline in percent of time spent in standing position as measured by a wearable device at Week 6 post randomization [6-week randomized withdrawal period (Week 16 to Week 22)]
A wearable device, such as an activity monitor, that provides date- and time-stamped activity information will be used to collect raw motion data to measure the time spent in supine, sitting, and standing positions.
Change from baseline in average number of steps taken as measured by a wearable device at Week 6 post randomization [6-week randomized withdrawal period (Week 16 to Week 22)]
A wearable device, such as an activity monitor, that provides date- and time-stamped activity information will be used to collect raw motion data to measure the time spent in supine, sitting, and standing positions.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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. No minimum score of OHSA#1 is required to enter V1 of Study 0170.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Sun Health Research Institute	Sun City	Arizona	United States	85351
2	UC San Diego Movement Disorder Center	La Jolla	California	United States	92307
3	Stanford Neuroscience Health Center	Palo Alto	California	United States	94304
4	Colorado Springs Neurological Associates, PC	Colorado Springs	Colorado	United States	80907
5	Parkinson's Disease and Movement Disorders Center	Boca Raton	Florida	United States	33486
6	SFM Clinical Research, LLC	Boca Raton	Florida	United States	33487
7	Neurostudies, Inc	Port Charlotte	Florida	United States	33952
8	Rush University Medical Center	Chicago	Illinois	United States	60612
9	NorthShore University Health System	Glenview	Illinois	United States	60026
10	University of Kansas Medical Center Research Institute, Inc.	Kansas City	Kansas	United States	66160
11	Mayo Clinic	Rochester	Minnesota	United States	55905
12	New York University Langone Health	New York	New York	United States	10016
13	Wake Forest University Baptist Health Sciences	Winston-Salem	North Carolina	United States	27157
14	University of Cincinnati Medical Center (UCGNI)	Cincinnati	Ohio	United States	45219
15	Ohio State University - Wexner Medical Center	Columbus	Ohio	United States	43210
16	Oregon Health & Science University	Portland	Oregon	United States	97239
17	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
18	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
19	Georgetown University Hospital	McLean	Virginia	United States	22101
20	Inland Northwest Research	Spokane	Washington	United States	99202
21	Ineba - Instituto de Neurociencias de Buenos Aires	Buenos Aires		Argentina	C1192AAW
22	Complejo Médico de la Policía Federal Argentina Churruca Visca	Buenos Aires		Argentina	C14375CP
23	STAT Research	Cuidad Autonoma de Buenos Aires		Argentina
24	Concord Hospital, Neurosciences Department	Concord	New South Wales	Australia	02139
25	Clinical Trials Centre, Level 3 Monash Health Translational Precinct Building Monash Medical Centre	Clayton	Victoria	Australia	3168
26	The Royal Melbourne Hospital Neurology Department	Parkville	Victoria	Australia	3050
27	Perron Institute for Neurological and Translational Science	Nedlands	Western Australia	Australia	6009
28	Medizinische Universitat Innsbruck, Abteilung fur Neurologie	Innsbruck		Austria	6020
29	Universitatsklinikum Tulln Abteilung fur Neurologie	Tulln		Austria	3430
30	MHATNP Sv. Naum EAD Clinic of Neurological Diseases for Locomotor Disorders	Sofia		Bulgaria	1113
31	University of Calgary Teaching Research and Wellness Building	Calgary	Alberta	Canada	T2N 4Z6
32	Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8
33	Montreal Neurological Institute & Hospital	Montreal	Quebec	Canada	H3A 2B4
34	Bispebjerg Hospital	Copenhagen		Denmark	2400
35	Odense Universitetshospital	Odense		Denmark	5000
36	East Tallinn Central Hospital	Tallinn		Estonia	10138
37	Astra Team Clinic	Tallinn		Estonia	11315
38	Tartu University Hospital	Tartu		Estonia	50406
39	CHU de Nîmes - Hôpital Caremeau	Nîmes		France	30029
40	Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin	Berlin		Germany	12203
41	Charite - Campus Virchow-Klinikum, Klinik fur Neurologie	Berlin		Germany	13353
42	Praxis Dr. med. Christian Oehlwein	Gera		Germany	7551
43	Semmelweis Egyetem, Neurologiai Klinika	Budapest		Hungary	1083
44	Rabin Medical Center, Beilinson Campus	Petah Tikva		Israel	4941492
45	Kaplan Medical Center	Rehovot		Israel	76100
46	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	6423906
47	Universita di Bologna-Clinica Neurologica - Dipt di Scienze Neurologiche Ospedale Bellaria	Bologna		Italy	40139
48	Azienda Ospedaliera Universitaria Policlinico - Vittorio Emanuele (Presidio Gaspare Rodolico)	Catania		Italy	95125
49	Universita degli studi Gabriele D' Annunzio Chieti	Chieti		Italy	66100
50	Fondazione IRCCS CA Granda Ospedale Maggiore Policlinico	Milano		Italy	20122
51	Azienda Ospedaliero-Universitaria Pisana- Ospedale S. Chiara, U.O. di Neurologia - Neurofisiopatologia	Pisa		Italy	56126
52	Fondazione PTV - Policlinico Tor Vergata I U.0.C. Neurologia	Roma		Italy	00133
53	Fondazione Policlinico Universitario Agostino Gemelli IRCCS / Istituto di Neurologia - Ambulatorio Disturbi del Movimento	Roma		Italy	00168
54	AOU San Giovanni di Dio e Ruggi d'Aragona	Salerno		Italy	84131
55	A.O. Santa Maria	Terni		Italy	05100
56	New Zealand Brain Research Institute	Christchurch		New Zealand	8011
57	Specjalistyczna Praktyka Lekarska, Prof. Grzegorz Opala	Katowice		Poland	40-588
58	Krakowska Akademia Neurologii Sp. Zo.o. Centrum Neurologii Klinicznej	Kraków		Poland	31-505
59	Instytut Zdrowia dr Boczarska-Jedynak	Oswiecim		Poland	32-600
60	NEURO-CARE Sp. z o.o. Sp. Komandytowa	Siemianowice Śląskie		Poland	41-100
61	ETG Warszawa	Warszawa		Poland	02-777
62	Specjalistyczne Gabinety sp. z o.o.	Warszawa		Poland	30-539
63	Hospital da Senhora da Oliveira Guimarães	Guimarães		Portugal	4835-044
64	CNS-Campus Neurologico Senior	Torres Vedras		Portugal	2560-280
65	Saint Petersburg State Budgetary Institution of Healthcare City Hospital #40 of Kurortnyi Region	Saint Petersburg	Sestroretsk	Russian Federation	197706
66	FSBI Federal Sibirian Scientific and Clinical Center of Federal Medico-Biological Agency	Krasnoyarsk		Russian Federation	660037
67	State Budgetary Institution of Healthcare of Novosibirsk region City Clinical Hospital #34	Novosibirsk		Russian Federation	630054
68	City Neurological Center Sibneiromed, LLC	Novosibirsk		Russian Federation	630091
69	FSBI National Medical Research Centre of psychiatry and neurology named after V.M. Bekhterev of the MOH of the Russian Federation	Saint Petersburg		Russian Federation	192019
70	FSBI of Science Institute of Human Brain named after N .P. Bekhtereva of Russian Academy of Sciences	Saint Petersburg		Russian Federation	197376
71	Hospital Universitario Mutua de Terrasa	Terrassa	Barcelona	Spain	08221
72	Complejo Hospitalario de Navarra	Pamplona	Navarra	Spain	31008
73	Hospital de Cruces	Bilbao	Vizcaya	Spain	48903
74	Hospital del Mar	Barcelona		Spain	08003
75	Hospital Universitario de La Princesa	Madrid		Spain	28006
76	Communal Noncommercial Enterprise City Policlinic #9 of Kharkiv City Council	Kharkiv		Ukraine	61172
77	Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital	Lviv		Ukraine	79010
78	Communal Institution Acad. O.I. Yuschenko VRPsH Vinnytsia M.I. Pyrogov NMU Ch of ND with the Course of Neurosurgery	Vinnytsia		Ukraine	21005
79	Royal Devon and Exeter Hospital NHS Trust	Exeter	Devon	United Kingdom	EX2 5DW
80	Cognition Health Unit 2	Plymouth	Devon	United Kingdom	PL6 8BT
81	Salford Royal NHS Foundation Trust	Salford	Greater Manchester	United Kingdom	M6 8HD
82	Clinical Research Centre, William Harvey Heart Centre	London		United Kingdom	EC1M 6BQ
83	King's College Hospital	London		United Kingdom	SE5 9RS
84	Re:Cognition Health Ltd	London		United Kingdom	W1G 9JF
85	The National Hospital for Neurology & Neurosurgery	London		United Kingdom	WC1N 3BG