td-9855 phase 2 in neurogenic orthostatic hypotension (noh)

Conditions: Neurogenic Orthostatic Hypotension; Multiple System Atrophy (MSA) With Orthostatic Hypotension; Pure Autonomic Failure; Parkinson Disease; Hypotension, Orthostatic; Orthostatic Hypotension; Pure Autonomic Failure With Orthostatic Hypotension; Parkinson Disease With Orthostatic Hypotension

Summary: this multiple-center, 3-part, single-blind dose escalation (part a), randomized, double-blind (part b), and open-label multiple dose extension (part c) study will be conducted in male and female subjects with neurogenic orthostatic hypotension to evaluate the effect of td-9855 in improving symptoms of orthostatic intolerance.

part a followed a daily, single-escalating-dose design, starting with placebo on day 1, followed by a dose of 2.5 mg td-9855 on day 2, and proceeding to higher daily doses of td-9855 up to a maximum dose of 20 mg based on safety, tolerability, and determination of a pressor effect. the starting dose in part a was initially set to 1 mg (day 2), escalating to a maximum dose of 10 mg (day 5), but this was revised to start at 2.5 mg (day 2) and escalate to 20 mg (day 5) in protocol amendment 2 (section 9.8.1). part b followed a randomized, placebo-controlled, parallel design, evaluating an acute dose of td-9855 that was determined to have a pressor effect and to be generally well tolerated for a given subject from part a. subjects who completed part a, demonstrated a pressor effect in part a, and remained otherwise eligible, had the option to receive open-label td-9855 by tablet daily for up to 5 months (20 weeks) during part c.

Eligibility criteria:
inclusion criteria: * diagnosed with symptomatic orthostatic hypotension due to parkinson's disease, multiple system atrophy, or pure autonomic failure, (i.e. neurogenic orthostatic hypotension). * at screening, subject must meet the diagnostic criteria of neurogenic orthostatic hypotension, as demonstrated by a ≥ 30 mm hg drop in systolic blood pressure (sbp) within 5 minutes of standing. * impaired autonomic reflexes, as determined by absence of bp overshoot during phase iv of the valsalva maneuver, in subjects where valsalva is performed, as appropriate. * for the optional open-label extension study subjects must have demonstrated a pressor effect and completed dosing in part a. exclusion criteria: * systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies. * concomitant use of vasoconstricting agents for the purpose of increasing bp such as ephedrine, dihydroergotamine, or midodrine must be stopped at least 2 days or five half lives (whichever is longer) prior to dosing on day 1 of part a and c, and throughout the duration of part c. subjects previously enrolled in part a under previous versions of the protocol will continue taking fludrocortisone during the washout period and in part c at the dose and regimen used in part a. for new subjects enrolling in part a under amendment 3, fludrocortisone use in both parts of the study and during the washout period will be limited to 0.1 mg qd. * concomitant use of anti-hypertensive medication for the treatment of essential hypertension unrelated to autonomic dysfunction. * known or suspected alcohol or substance abuse within the past 12 months.

Keywords: neurogenic orthostatic hypotension (noh) multiple system atrophy (msa) pure autonomic failure parkinson disease(pd) noh msa pd paf orthostatic hypotension ampreloxetine td-9855