Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy

Figures

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  Figure 1. CONSORT Flow Diagram Patient flow for the multiple system atrophy (MSA) subgroup enrolled in SEQUOIA, which was a 4-week randomized control trial, and randomized withdrawal (REDWOOD), which was a randomized withdrawal (RW) study with 16 weeks of open-label treatment followed by 6-week RW. Most participants rolled over into REDWOOD from SEQUOIA, and 2 participants entered REDWOOD as de novo. After SEQUOIA did not meet the primary endpoint, REDWOOD was early terminated by the sponsor, which is indicated in the discontinuation reason as “sponsor-driven discontinuation.” The prespecified subgroup analysis of the REDWOOD RW period included 40 MSA participants who were randomized into the withdrawal phase. *Both patients who enrolled de novo into REDWOOD were terminated early in the open-label phase by the sponsor because of closure of the trial after SEQUOIA did not reach the primary endpoint and therefore were not included in the analysis set. AE = adverse event; FAS = full-analysis set; MSA = multiple system atrophy; OL = open-label; RW = randomized withdrawal; QD = once daily.

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  Figure 2. Study Design The prespecified subgroup analysis was performed in participants enrolled with a diagnosis of multiple system atrophy (MSA) and symptomatic neurogenic orthostatic hypotension (nOH), approved by an Enrollment Steering Committee, who met the cutoff for preserved peripheral (sympathetic) autonomic neurons (plasma norepinephrine (NE) ≥ 100 pg/mL). Approved participants were enrolled in a 4-week double-blind, placebo-controlled, randomized clinical trial of ampreloxetine (SEQUOIA). After completion, participants rolled over into randomized withdrawal (REDWOOD), which included a 16-week open-label period, with 2 enrichment points (week 4 and week 16). Participants who met open-label enrichment criteria underwent randomized withdrawal (RW) with 1:1 allocation to placebo or ampreloxetine for 6 weeks. The analysis of the efficacy outcome measures was performed at the end of each double-blind phase. SEQUOIA was designed to show benefit of ampreloxetine over placebo using the Orthostatic Hypotension Questionnaire (OHQ) item 1. REDWOOD was designed to show worsening after withdrawal to placebo in a composite treatment failure endpoint (1 point worsening of OHQ item 1 and a…

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  Figure 3. MSA Subgroup Patient-Reported Outcome Measures (A) Forest plot indicates odds of treatment failure (top) and least squares mean difference in Orthostatic Hypotension Questionnaire (OHQ) self-reported symptoms scores (bottom) at the end of the 6-week randomized withdrawal (RW). (B) Longitudinal analysis of mean OHQ symptom assessment composite scores, after censorship for early withdrawal, in the subgroup of randomized patients with multiple system atrophy (MSA) (n = 40). Note that benefit (lower scores) observed in open-label was maintained in the MSA group randomized to ampreloxetine (n = 20), but lost (i.e., increasing back to baseline) in the group withdrawn to placebo (n = 20). (C) Orthostatic Hypotension Daily Activities Scale (OHDAS) item 1 scores capturing severity of interference of symptoms of neurogenic orthostatic hypotension (nOH) on standing for a short time, which showed a similar pattern with improvement on open-label, that worsening by the end of the RW in the placebo arm. LS = least squares; OHDAS = OH daily activity scale; OHQ = orthostatic hypotension questionnaire; OHSA = OH Symptom assessment; RW = randomized withdrawal; SEM = standard error of the mean; Tx =…

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  Figure 4. Norepinephrine and Blood Pressure (A) Venous plasma norepinephrine (NE) levels (seated) at baseline and at the end of the 4-week double-blind randomized controlled trial (RCT) period of SEQUOIA. (B) Longitudinal analysis of blood pressure (BP) at 3 minutes of standing at entry (pretreatment baseline), throughout the 16-week open-label period, and in the randomized withdrawal (RW) in the analysis population set of REDWOOD. (C) Absolute systolic BP after 10 minutes of supine rest and after 3 minutes of standing at week 6 of the RW. (D) Absolute diastolic blood pressure (DBP) after 10 minutes of supine rest and after 3 minutes of standing at week 6 of the RW. (E) Absolute HR after 10 minutes of supine rest and after 3 minutes of standing at week 6 of the RW. †p values vs placebo are based on least squared (LS) mean difference in change between the start and end of RW. Note that the minimal effect of ampreloxetine on supine BP with lower standing blood pressures and HR in the placebo group. DBP = diastolic BP; HR = heart rate; NE = norepinephrine; OL = open-label; RW = randomized withdrawal; SBP = systolic BP; SEM = standard error of the mean.