Impact of Nuedexta on Bulbar Physiology and Function in ALS

• ClinicalTrials.gov Identifier: NCT03883581
• Recruitment Status: Completed
• First Posted: March 21, 2019
• Results First Posted: March 8, 2023
• Last Update Posted: March 8, 2023
• Sponsor: University of Florida
• Collaborators: Holy Cross Hospital, Florida; ALS Association
• Information provided by (Responsible Party): University of Florida

Tracking Information

• First Submitted Date: March 12, 2019
• First Posted Date: March 21, 2019
• Results First Submitted Date: September 12, 2022
• Results First Posted Date: March 8, 2023
• Last Update Posted Date: March 8, 2023
• Actual Study Start Date: July 25, 2019
• Actual Primary Completion Date: September 13, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2023)

• 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).
• 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.
• 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 1-5 with 5 considered the worst. For the speech domain, individuals who are unable to speak are assigned a value of 6 for each item (speech domain ranges from 1-6). Total scores ranging from 21 (no impairment) - 112 (severe impairment in all domains).
• Change in ALSFRS-R Bulbar Subscale Score [ Time Frame: Baseline; Day 30 ]
  The ALS Functional Rating Scale-Revised Bulbar subscore is an outcome comprised of questions 1-3 on the validated ALSFRS-R scale. These items rate speech, swallowing and salivation functions on a scale from 0-total loss of function to 4- no symptoms for a total score of 0 to 12.
• Bamboo Passage Reading Duration (in Seconds) [ Time Frame: Baseline; Day 30 ]
  The Bamboo Passage is a 60-word reading passage that is commonly used to measure speech duration.

Original Primary Outcome Measures (submitted: March 19, 2019)

• 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).
• 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.
• 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.
• 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.
• 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).

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Impact of Nuedexta on Bulbar Physiology and Function in ALS
• Official Title: Impact of Nuedexta on Bulbar Physiology and Function in ALS
• 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.
• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis

Intervention

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

Study Arms

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.

Intervention: Drug: dextromethorphan HBr and quinidine sulfate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 8, 2021): 28
• Original Estimated Enrollment (submitted: March 19, 2019): 40
• Actual Study Completion Date: November 22, 2021
• Actual Primary Completion Date: September 13, 2021 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03883581
• Other Study ID Numbers: IRB201802938; OCR20392 ( Other Identifier: UF OnCore )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Florida
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Florida
• Original Study Sponsor: Same as current

Collaborators

• Holy Cross Hospital, Florida
• ALS Association

Investigators

• Principal Investigator: Lauren Tabor, PhD; Phil Smith Neuroscience Institute at Holy Cross Hospital
• Principal Investigator: Emily Plowman, PhD; University of Florida

• PRS Account: University of Florida
• Verification Date: February 2023