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Impact of Nuedexta on Bulbar Physiology and Function in ALS

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ClinicalTrials.gov Identifier: NCT03883581
Recruitment Status : Not yet recruiting
First Posted : March 21, 2019
Last Update Posted : March 28, 2019
Sponsor:
Collaborators:
Holy Cross Hospital, Florida
ALS Association
Information provided by (Responsible Party):
University of Florida

Brief Summary:
Nuedexta is FDA approved for the treatment of pseudobulbar affect in ALS patients and anecdotal reports of improvements in speech, salivation or swallowing have been reported. However, no prospective study has been conducted to comprehensively examine and determine the physiologic impact of Nuedexta on both speech and swallowing physiology in a large group of ALS individuals. These data are needed in order to provide evidence-based guidance to the management of bulbar dysfunction in ALS.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: dextromethorphan HBr and quinidine sulfate Phase 1 Phase 2

Detailed Description:
Although advances in the management of bulbar dysfunction in ALS have been disappointing, recent interest has surfaced regarding the therapeutic potential of a pharmaceutical agent, Nuedexta (dextromethorphan HBr and quinidine sulfate), for the treatment of bulbar symptomology in individuals with ALS. Although Nuedexta received approval from the Food and Drug Administration (FDA) to target symptoms of pseudobulbar affect (PBA) in ALS; anecdotal reports of improvements in speech, salivation or swallowing were reported from Neurologists treating ALS individuals who were administered Nuedexta. Subsequently, a Phase II clinical trial was conducted that reported improvements in speech, swallowing and salivation following 30-days of Nuedexta treatment. One serious limitation of this study, however, is the fact that the primary outcome employed was a perceptual patient-report scale (PRO) (Center for Neurological Study Bulbar Function Scale, CNS-BFS), with no objective physiologic outcomes to confirm actual change in bulbar physiology. The absence of any objective clinical physiologic outcomes is particularly important when examining effects of Nuedexta, given that it contains selective serotonin reuptake inhibitors (SSRIs), or serotonergic antidepressants, that can impact the regulation of emotional expression, feelings of wellbeing and modulation of depression (all known to impact the response an individual will provide on a PRO measure). Furthermore, findings based on PRO's must be validated with studies that utilize objective physiologic outcomes of speech and swallowing function. Great excitement exists regarding the potential impact of Nuedexta on bulbar function in ALS with many neurologists prescribing Nuedexta to treat these symptoms in ALS patients. To date, however; no data exists to examine and determine the physiologic impact of Nuedexta on speech or swallowing physiology. These data are needed in order to validate the initial patient-reported outcomes of the Phase II clinical trial and to provide evidence-based guidance to the management of bulbar dysfunction in ALS.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Impact of Nuedexta on Bulbar Physiology and Function in ALS
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : February 28, 2021


Arm Intervention/treatment
Experimental: ALS individuals with bulbar dysfunction
Participants enrolled in this group will be prescribed dextromethorphan HBr and quinidine sulfate (Nuedexta) as recommended by their treating neurologist. 20 mg dextromethorphan HBr and 10mg quinidine sulfate will be administered orally with 1 capsule every day for the initial 7 days followed by 1 capsule every 12 hours for the remaining 23 days of the study. Participants will be evaluated 30 days apart to determine the impact of treatment.
Drug: dextromethorphan HBr and quinidine sulfate
All eligible and enrolled study participants will be administered the study drug, Nuedexta, as recommended by their treating neurologists.The drug will be administered per the efficacy and safety protocol, with no changes in administration method or recommended dose for individuals with ALS. Prior to commencing treatment with Nuedexta, participants will undergo a comprehensive bulbar evaluation of swallowing, airway protection, speech functions, and complete validated patient-reported surveys. Following 30 days of Nuedexta treatment, participants will be e-evaluated using the same battery of assessments.
Other Name: Nuedexta




Primary Outcome Measures :
  1. Change in Dynamic Imaging Grade of Swallowing Toxicity [ Time Frame: Baseline; Day 30 ]
    The validated Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) will be performed on all collected videofluoroscopic swallowing studies to assess global swallowing function. The DIGEST total score is determined using the composite of individual airway safety and bolus efficiency subscores (range: 0-4). The DIGEST total is rated on a 5-point ordinal score ranging from 0 (no dysphagia) to 4 (life-threatening dysphagia).

  2. Change in Airway Physiologic Defense Capacity [ Time Frame: Baseline; Day 30 ]
    Peak expiratory cough flow will be collected during maximum effort voluntary cough testing. Peak expiratory cough flow is calculated as the flow rate (L/s/s) between the end point of the compression phase of cough to the point of maximum expiration. Three trials will be performed at each evaluation and the maximum flow rate of the three epochs will be utilized for statistical analysis.

  3. Change in Speech Intelligibility [ Time Frame: Baseline; Day 30 ]
    The Sentence Intelligibility Test (SIT) will be performed to assess the change in speaking intelligibility over the 30 day period. The primary outcome of the SIT will be the percentage of sentence intelligibility (%) during oral reading.

  4. Change in maximum isometric lingual strength [ Time Frame: Baseline; Day 30 ]
    The Iowa Oral Performance instrument will be utilized to assess maximum isometric lingual strength (kPa) at each evaluation. Three trials will be completed at each evaluation and the maximum of the three trials will be utilized for statistical analysis.

  5. Change in Patient-reported outcome: Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) [ Time Frame: Baseline; Day 30 ]
    The CNS-BFS is a validated patient-reported scale that assess self-reported impairments in the domains of speech, salivation and swallowing. Each domain contains 7 questions with ratings ranging from 1-7 with 7 considered the worst, with total scores ranging from 21 (no impairment) - 112 (severe impairment in all domains).



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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of probable-definite ALS (El-Escorial Criterion);
  • ALSFRS-R Bulbar subscale score <10
  • Bamboo oral reading speaking rate <140 words per minute
  • No allergies to barium sulfate.

Exclusion Criteria:

  • Treatment for sialorrhea within the past 3 months that includes either Botox or radiation treatment
  • Participation in another disease modifying study targeting bulbar or cough function
  • Use of invasive mechanical ventilation/presence of tracheostomy
  • Advanced frontotemporal dementia or significant cognitive dysfunction
  • Nil per oral status for feeding (i.e., NPO, nothing by mouth)
  • Previously prescribed Nuedexta. Additionally, if participants are taking Riluzole or other medications to control sialorrhea, they must be on a stable dose for at least 30 days prior to enrollment in the current study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03883581


Contacts
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Contact: Kelby Magennis, MPH 352-273-8632 kmagennis@phhp.ufl.edu

Locations
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United States, Florida
Phil Smith Neuroscience Institute at Holy Cross Hospital Not yet recruiting
Fort Lauderdale, Florida, United States, 33308
Contact: Lauren Tabor, PhD    954-542-3429    lauren.tabor@holy-cross.com   
University of Florida Not yet recruiting
Gainesville, Florida, United States, 32610
Contact: Kelby Magennis, MPH    352-273-8632    kmagennis@phhp.ufl.edu   
Sponsors and Collaborators
University of Florida
Holy Cross Hospital, Florida
ALS Association
Investigators
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Principal Investigator: Lauren Tabor, PhD Phil Smith Neuroscience Institute at Holy Cross Hospital
Principal Investigator: Emily Plowman, PhD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03883581     History of Changes
Other Study ID Numbers: IRB201802938
OCR20392 ( Other Identifier: UF OnCore )
First Posted: March 21, 2019    Key Record Dates
Last Update Posted: March 28, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of Florida:
bulbar dysfunction

Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Dextromethorphan
Quinidine
Quinidine gluconate
Antitussive Agents
Respiratory System Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Anti-Arrhythmia Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Muscarinic Antagonists