Amyotrophic Lateral Sclerosis
Conditions
Keywords
bulbar dysfunction
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.
Interventions
DRUGdextromethorphan 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.
Sponsors
Holy Cross Hospital, Florida
ALS Association
University of Florida
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Dynamic Imaging Grade of Swallowing Toxicity | 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 | 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) | 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 | 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) | Baseline; Day 30 | The Bamboo Passage is a 60-word reading passage that is commonly used to measure speech duration. |
Countries
United States
Participant flow
Recruitment details
All recruitment and enrollment took place at the Phil Smith Neuroscience Institute. Recruitment began in July 25, 2019 and ended in August 2021
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | ALS Individuals With Bulbar Dysfunction |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 64.75 years STANDARD_DEVIATION 9.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 4 / 28 |
| serious Total, serious adverse events | 1 / 28 |
Outcome results
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Individuals With Bulbar Dysfunction | Bamboo Passage Reading Duration (in Seconds) | Pre Nuedexta | 66.19 Seconds | Standard Error 3.59 |
| ALS Individuals With Bulbar Dysfunction | Bamboo Passage Reading Duration (in Seconds) | Post Nuedexta | 65.33 Seconds | Standard Error 3.59 |
p-value: 0.103Paired t test
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Individuals With Bulbar Dysfunction | Change in ALSFRS-R Bulbar Subscale Score | Pre Nuedexta | 7.47 score on a scale | Standard Error 0.38 |
| ALS Individuals With Bulbar Dysfunction | Change in ALSFRS-R Bulbar Subscale Score | Post Nuedextaa | 8.39 score on a scale | Standard Error 0.37 |
p-value: 0.0004Wilcoxon (Mann-Whitney)
Primary
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALS Individuals With Bulbar Dysfunction | Change in Dynamic Imaging Grade of Swallowing Toxicity | Post Nuedexta DIGEST 0 (Normal) | 7 Participants |
| ALS Individuals With Bulbar Dysfunction | Change in Dynamic Imaging Grade of Swallowing Toxicity | Pre Nuedexta DIGEST 0 (Normal) | 3 Participants |
p-value: 0.08Wilcoxon (Mann-Whitney)
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Individuals With Bulbar Dysfunction | Change in Patient-reported Outcome: Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) | Pre Nuedexta | 56.87 Score | Standard Error 3.01 |
| ALS Individuals With Bulbar Dysfunction | Change in Patient-reported Outcome: Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) | Post Nuedexta | 54.13 Score | Standard Error 2.97 |
p-value: 0.103Paired t test
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Individuals With Bulbar Dysfunction | Change in Speech Intelligibility | Pre Nuedexta | 71.52 Percent Intelligibility | Standard Error 6.62 |
| ALS Individuals With Bulbar Dysfunction | Change in Speech Intelligibility | Post Nuedexta | 73.06 Percent Intelligibility | Standard Error 6.15 |
p-value: 0.647Paired t test