A Phase 1/2 interventional study of dextromethorphan HBr and quinidine sulfate in Amyotrophic Lateral Sclerosis, sponsored by University of Florida. Completed at 2 sites in United States. Open to participants aged 18 Years to 90 Years. Per ClinicalTrials.gov, last updated 2023-03-08.
Sponsored by University of Florida · Phase 1/2, Interventional, and Treatment
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.
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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Exclusion Criteria:
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.
Also known as: Nuedexta
Change in Dynamic Imaging Grade of Swallowing Toxicity
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).
Time frame: Baseline; Day 30
Change in Speech Intelligibility
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.
Time frame: Baseline; Day 30
Change in Patient-reported Outcome: Center for Neurologic Study-Bulbar Function Scale (CNS-BFS)
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).
Time frame: Baseline; Day 30
Change in ALSFRS-R Bulbar Subscale Score
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.
Time frame: Baseline; Day 30
Bamboo Passage Reading Duration (in Seconds)
The Bamboo Passage is a 60-word reading passage that is commonly used to measure speech duration.
Time frame: Baseline; Day 30
All recruitment and enrollment took place at the Phil Smith Neuroscience Institute. Recruitment began in July 25, 2019 and ended in August 2021
| Milestone | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Started | 28 |
| Completed | 24 |
| Not completed | 4 |
| Withdrew: Withdrawal by subject | 4 |
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).
| Participants | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Pre Nuedexta DIGEST 0 (Normal) | 3 |
| Post Nuedexta DIGEST 0 (Normal) | 7 |
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.
| Percent Intelligibility | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Pre Nuedexta | 71.52 ± 6.62 |
| Post Nuedexta | 73.06 ± 6.15 |
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).
| Score | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Pre Nuedexta | 56.87 ± 3.01 |
| Post Nuedexta | 54.13 ± 2.97 |
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.
| score on a scale | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Pre Nuedexta | 7.47 ± 0.38 |
| Post Nuedextaa | 8.39 ± 0.37 |
The Bamboo Passage is a 60-word reading passage that is commonly used to measure speech duration.
| Seconds | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Pre Nuedexta | 66.19 ± 3.59 |
| Post Nuedexta | 65.33 ± 3.59 |
Collected over Adverse events were collected from time of enrollment to study trial completion (30 days).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| ALS Individuals With Bulbar Dysfunction | 0/28 (0%) | 1/28 (3.6%) | 4/28 (14.3%) |
| Event | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Prolonged hospitalization due to left leg DVTGeneral disorders | 1/28 |
| Event | ALS Individuals With Bulbar Dysfunction |
|---|---|
| FaintingGeneral disorders | 1/28 |
| DiarrheaGastrointestinal disorders | 1/28 |
| HeadacheGeneral disorders | 1/28 |
| NauseaGeneral disorders | 1/28 |
| Age, Categorical(Participants) | ALS Individuals With Bulbar Dysfunction |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 12 |
| >=65 years | 16 |
| Age, Continuous(years) | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Mean | 64.75 ± 9.18 |
| Sex: Female, Male(Participants) | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Female | 11 |
| Male | 17 |
| Ethnicity (NIH/OMB)(Participants) | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Hispanic or Latino | 2 |
| Not Hispanic or Latino | 26 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | ALS Individuals With Bulbar Dysfunction |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 3 |
| White | 23 |
| More than one race | 2 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | ALS Individuals With Bulbar Dysfunction |
|---|---|
| United States | 28 |
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