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Nuedexta Bulbar Function Trial

Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial

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Year of Publication: 2017

Authors: Richard Smith, Erik Pioro, Kathleen Myers, ..., Gary Pattee

Journal: Neurotherapeutics

Citation: Neurotherapeutics (2017) 14:762-772

Link: https://doi.org/10.1007/s13311-016-0508-5

Clinical Question

Does Nuedexta (dextromethorphan/quinidine) exert a palliative effect on speech, swallowing, and salivation in patients with ALS?

Bottom Line

Nuedexta significantly improved bulbar function in ALS patients, with improvements in all three domains (speech, swallowing, salivation) as measured by the CNS-BFS. The effect was independent of pseudobulbar affect status, suggesting a direct benefit on bulbar motor neuron function.

Major Points

  • This is the first controlled study to report improvement of bulbar function (speech, swallowing, salivation) in ALS
  • The primary endpoint CNS-BFS score improved from 59.3 (placebo) to 53.5 (active treatment), a difference of -5.85 points (p<0.001)
  • All three bulbar domains improved significantly: salivation (p=0.004), speech (p=0.003), swallowing (p=0.009)
  • The ALSFRS-R bulbar component also improved (p=0.003), but motor and respiratory components were unaffected
  • Treatment effect was independent of pseudobulbar affect (PBA) status - patients with and without PBA both benefited
  • Approximately 49% of patients improved ≥1 point on ALSFRS-R bulbar domain with DMQ vs 26% on placebo
  • The study was driven by patient reports of improved speech/swallowing while taking Nuedexta for emotional lability
  • Trial used a novel self-report scale (CNS-BFS) as primary outcome, which proved more sensitive than quantitative measures

Design

Study Type: Phase II, multicenter, double-blind, randomized crossover trial

Randomization: 1

Blinding: Double-blind. Study patients, site investigators, and all study staff including project and data management personnel and study sponsor were blinded. Research pharmacists who prepared and shipped drug supplies were unblinded.

Enrollment Period: April 2013 to November 2014

Follow-up Duration: 70 days total (28-30 days per treatment arm with 10-15 day washout)

Centers: 7

Countries: United States

Sample Size: 60

Analysis: Analysis of covariance with terms for baseline value, treatment group, and period sequence. Patients' mean CNS-BFS scores modeled as random effect. Estimates calculated by least-squared means with SEs. Tested for period-treatment interaction to allow for carry-over effect. Intent-to-treat analysis. 88% power to detect treatment difference at 2-sided 0.05 significance level.

Inclusion Criteria

  • Age ≥18 years
  • Diagnosis of probable or definite ALS per revised World Federation of Neurology El Escorial criteria
  • Disease duration <2 years from time of diagnosis
  • Bulbar dysfunction manifested by dysarthria and/or dysphagia as determined by site PI
  • CNS-BFS score ranging from 50 to 80
  • Slow vital capacity ≥50% of normal
  • Intact cognitive function as determined by PI
  • Relatively sound general health based on physical examination and baseline laboratory values
  • If taking riluzole, must be on drug for ≥30 days prior to randomization
  • If taking medication(s) to control salivation, must be on stable dose for ≥30 days prior

Exclusion Criteria

  • Prior use of Nuedexta (DMQ)
  • Current use of dextromethorphan, quinidine, quinine, mefloquine, or opioids
  • Known sensitivity to dextromethorphan, quinidine, quinine, mefloquine, or opioids
  • History of prolonged QT interval
  • Congenital long QT syndrome
  • Complete atrioventricular block
  • Concomitant use of drugs that both prolong QT interval and are metabolized by CYP2D6
  • Use of monoamine oxidase inhibitors
  • Invasive ventilator dependence
  • Use of a feeding tube
  • Treatment with Botox for control of sialorrhea within 90 days of screening
  • Treatment with radiation for control of sialorrhea within 180 days of screening

Arms

FieldNuedexta (DMQ) Treatment ArmControl
InterventionNuedexta (dextromethorphan hydrobromide 20mg + quinidine sulfate 10mg). One capsule in the evening for 7 days, then 2 capsules per day at 12-hour intervals for remaining 21 days.Placebo capsules identical in appearance to Nuedexta. One capsule in the evening for 7 days, then 2 capsules per day at 12-hour intervals for remaining 21 days.
Duration28-30 days28-30 days

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in Center for Neurologic Study Bulbar Function Scale (CNS-BFS) total score. The CNS-BFS is a 21-item self-report scale assessing 3 domains: speech, swallowing, and salivation (score range 21-112, lower is better).Primary59.31 (SE 1.10)53.45 (SE 1.07)<0.001
CNS-BFS Sialorrhea subscaleSecondary15.8114.280.004
CNS-BFS Speech subscaleSecondary24.5722.220.003
CNS-BFS Swallowing subscaleSecondary18.9217.140.009
ALSFRS-R Bulbar componentSecondary6.797.390.003
ALSFRS-R Total scoreSecondary33.7034.150.25
ALSFRS-R Motor componentSecondary16.8016.630.46
ALSFRS-R Respiratory componentSecondary10.1010.120.90
VAS SpeechSecondary4.114.970.005
VAS SwallowingSecondary6.937.230.47
VAS SialorrheaSecondary6.786.780.99
Words read per minuteSecondary103.37107.120.15
Average swallow water time (seconds)Secondary13.1112.160.33
Average swallow solids time (seconds)Secondary19.4518.530.58
CNS Lability Scale (CNS-LS) TotalSecondary13.7210.79<0.001
ConstipationAdverse2 events (2 subjects, 4%)5 events (5 subjects, 9%)
DiarrheaAdverse1 event (1 subject, 2%)5 events (5 subjects, 9%)
NauseaAdverse0 events (0 subjects, 0%)5 events (4 subjects, 7%)
DizzinessAdverse1 event (1 subject, 2%)10 events (7 subjects, 12%)
DeathAdverse01 (respiratory failure secondary to ALS)
Severe AEsAdverse3 events (3 subjects, 5%)2 events (2 subjects, 3%)

Subgroup Analysis

Patients were stratified by pseudobulbar affect (PBA) status at baseline (CNS-LS score >13). Both groups (with and without PBA) experienced equivalent improvement in CNS-BFS total scores with DMQ treatment. There was no significant correlation between baseline CNS-LS score and response to treatment (r = -0.054, p = 0.70). No center or period effects were observed.

Criticisms

  • Short study duration (70 days total) - does not address long-term durability of treatment effect
  • Small sample size (60 patients) limits power for subgroup analyses
  • Study not designed to predict duration of treatment effect or impact on disease progression
  • Phase II trial - requires Phase III confirmation
  • Crossover design may have carryover effects despite washout period
  • Self-report primary outcome may be subject to bias
  • Quantitative measures (speech rate, timed swallowing) did not reach statistical significance
  • 18 of 52 completers (35%) showed same or worse CNS-BFS scores with DMQ vs placebo
  • Population predominantly white (95%) and non-Hispanic (100%), limiting generalizability
  • Majority had bulbar onset ALS (63.3%), which may not represent typical ALS population
  • No effect on motor or respiratory function limits applicability to overall ALS management
  • Mechanism of action not fully elucidated

Funding

ALS Association through the Treat ALS award. Additional support from Lewis and Gladyce Foster Family Foundation and an anonymous donor to Massachusetts General Hospital Neurological Clinical Research Institute. Avanir Pharmaceuticals provided drug and placebo.

Based on: Nuedexta Bulbar Function Trial (Neurotherapeutics, 2017)

Authors: Richard Smith, Erik Pioro, Kathleen Myers, ..., Gary Pattee

Citation: Neurotherapeutics (2017) 14:762-772

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