A Study to Evaluate the Durability of TD-9855 for Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

Overview

About this study

The purpose of this study is to evaluate the durability effect of TD-9855 in subjects with symptomatic neurogenic orthostatic hypotension (snOH) due to multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) compared with placebo (PBO) over a double-blind, randomized withdrawal period of 6 weeks following an open label (OL) treatment of 16 weeks, and to evaluate the safety and tolerability of TD-9855 when taken for up to 22 weeks.

 

 

 

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 TD-9855. 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.
  • The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including an understanding that entry to Study 0170 may result in changes occurring in the subject’s current therapeutic regimen).
  • The subject must be willing to continue on treatment regardless of the possibility of randomization to either TD-9855 or PBO during the randomized withdrawal phase and must continue to meet the inclusion criteria for the preceding study (Study 0169) with the exception that tilt-table test, ESC review and approval of eligibility are not required for entry into Study 0170.

Inclusion Criteria (For De Novo Group): 

  • Subject is male or female and at least 30 years old;
  • Subject must meet the diagnostic criteria of snOH, as demonstrated by a ≥ 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 impaired autonomic reflexes, as determined by absence of Phase IV BP overshoot after release of the Valsalva strain. 
  • Subject has plasma Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated position for 30 minutes.
  • Subject is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
  • 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 (for 0169 Completers Group): 

  • Subject may not be enrolled in another clinical trial (other than exiting Study 0169).
  • Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of subjects to give informed consent or interfere with the conduct of the study.
  • Medical, laboratory, or surgical issues deemed by the Investigator to be clinically significant. 
  • 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 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:
    • Well controlled type-2 DM in treatment with only oral medications and diet;
    • HgbA1C of ≤ 7.5% performed during screening or up to 12 weeks before screening;
    • No clinically evident peripheral neuropathy (e.g., normal sensory examination on peripheral extremities);
    • No known retinopathy (e.g., annual ophthalmic exam is sufficient);
    • No nephropathy (e.g., absence of albuminuria and GFR > 60).
  • 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.
  • 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 had any malignant disease, other than carcinoma in situ of the cervix or basal cell carcinoma, within the past 2 years prior to screening.
  • 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).
  • 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.
  • 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]).
  • Subject has a clinically significant abnormal laboratory finding(s) (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 m^2 , 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 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.
  • 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.
  • Subject has known hypersensitivity to TD-9855 (ampreloxetine hydrochloride), or any excipients in the formulation.
  • Subject has:
    • confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) documented with coronavirus disease 2019 [COVID-19] positive test result; OR
    • 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
    • has been in close contact with a person with known (or suspected) SARS-CoV-2 infection and remains asymptomatic until Day 1.
  • At V3 (Week 4), following the initial 4-week OL treatment, subjects must demonstrate a reduction in OHSA#1 of at least 2 points compared to the baseline value, as determined in Study 0169 for subjects entering from Study 0169 and from V1 for de novo subjects, in order to continue in Study 0170.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Phillip Low, M.D.

Open for enrollment

Contact information:

Raelene Martini

(507) 284-0336

adc.research@mayo.edu

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

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