None listed
Conditions
Interventions
Beginning on Day 2, subjects will receive a single dose of 10-mg TD-9855 once daily (QD) and continue thereafter for the 16 week duration of the OL treatment period. Following this 16-week OL treatment period, subjects will be randomized to either continue on the active treatment or PBO for a period of 6 weeks.
Sponsors
Theravance Biopharma Ireland Limited,
Eligibility
Inclusion criteria
Inclusion criteria: 1. Subject is male or female and at least 30 years old. 2. If subject is female, the subject must be non-pregnant and non-lactating. 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 beta human chorionic gonadotropin (bHCG) 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 min of being tilted up ≥60o from a supine position as determined by a tilt-table test. 5. Subject must score at least a 4 on the OHSA#1 at V1. 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 understand clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.
Exclusion criteria
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 V1 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 V1. • Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1. 6. 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). 7. Subject has a clinically unstable coronary artery disease, or has had a 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 V1. 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 had 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 drug that is not approved by a regulatory agency (e.g., Food and Drug Administration [FDA]). 19. Subject has a clinically significant abnormal laboratory finding (e.g., alanine aminotransferase [ALT] or aspartate aminotransfera
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Outcome name:Sensitivity analyses on the primary endpoint will be carried out (1) using per-protocol set which excludes subjects with major protocol deviations, (2) using multiple imputation for subject missing OHSA#1 and/or PGI-S score at Week 6 post randomization (V9, D155) and (3) by excluding subjects with missing data on primary endpoint. Additional sensitivity analyses may be defined in the SAP. The primary analysis will be repeated on a set of pre-specified subgroups (e.g., disease type) and presented in graphical format. Details will be specified in the Statistical Analysis Plan (SAP). Measure:The primary study endpoint is the proportion of treatment failure at Week 6 during the double-blind randomized withdrawal phase. Treatment failure is defined as subjects who meet the following criteria at Week 6 following randomization (V9, D155): 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. The assessments done at the Week 16 (V6, D113) visit in the OL phase prior to randomization are considered baseline for the double blind randomized withdrawal phase of the study. Subjects who withdraw for any reason prior to V9 (D155) or subjects who fail to provide assessment at V9 (D155) will be considered as treatment failures. Timepoints:16 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Outcome name:Secondary efficacy endpoints will be tested via a statistical testing procedure, to be described in the statistical analysis plan (SAP), that will protect the family-wise Type I error rate at 2-sided significance level of 5%. • Change from baseline in OHSA composite score at Week 6 post randomization (V9, D155) • Change from baseline in OHSA item 1 score at Week 6 post randomization (V9, D155) • Change from baseline in OHDAS composite score at Week 6 post randomization (V9, D155) • Change from baseline in PGI-S at Week 6 post randomization (V9, D155) • Change from baseline in percent of time spent standing position as measured by a wearable device at Week 6 post randomization (V9, D155) • Change from baseline in average number of steps taken as measured by a wearable device at Week 6 post randomization (V9, D155) For all supportive analyses including sensitivity analyses of the primary efficacy endpoint and other efficacy endpoints, p-values and confidence intervals will be evaluated descriptively at two-sided 5% level with no adjustment for multiplicity.In addition descriptive analysis of efficacy data collected during OL phase will be carried out for all subjects and by enrollment group (De Novo Group or 0169 Completers Group). Safety data will be listed by subject and summarized using the frequency of event or descriptive statistical summaries, as appropriate. Summaries and listings will be presented separately for OL phase and double blinded randomized withdrawal phase. Summary tables will be provided for vital signs, body weight, ECGs, safety laboratory tests, C-SSRS, AEs, and concomitant medications. Measure:• Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155) • Change from baseline in OHSA composite score at Week 6 post randomization (V9, D155) • Change from baseline in OHDAS composite score at Week 6 post randomization (V9, D155) • Change from baseline in PGI-S at Week 6 post ra | — |
Countries
Argentina, Australia, Austria, Bulgaria, Canada, Chile, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, Mexico, New Zealand, Poland, Portugal, Russian Federation, Spain, Ukraine, United Kindgdom, United States
Contacts
Public ContactElizabeth Rospigliosi
RPS PERU S.A.C
Outcome results
None listed