Clinical Trial Nuedexta in Subjects With ALS

• ClinicalTrials.gov Identifier: NCT01806857
• Recruitment Status: Completed
• First Posted: March 7, 2013
• Results First Posted: March 24, 2017
• Last Update Posted: March 24, 2017
• Sponsor: Center for Neurologic Study, La Jolla, California,
• Collaborators: ALS Association; State University of New York - Upstate Medical University
• Information provided by (Responsible Party): Richard A. Smith, MD, Center for Neurologic Study, La Jolla, California,

Tracking Information

• First Submitted Date: March 5, 2013
• First Posted Date: March 7, 2013
• Results First Submitted Date: August 9, 2016
• Results First Posted Date: March 24, 2017
• Last Update Posted Date: March 24, 2017
• Study Start Date: April 2013
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2017)

• Bulbar Function Scale (CNS-BFS) Total Score [ Time Frame: Average between Screening Visit to Visit 3 ]
  The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the speech, swallowing and salivation (sialorrhea). [Range of score: 21-105] The scale was modeled on the Center for Neurologic Study Emotional Lability Scale (CNS-LS) that has been a robust endpoint in four clinical trials. The scale was validated in a large population of ALS patients (n=122) and detects impaired bulbar function at a sensitivity of 90% and a specificity of 0.97%. Test re-test correlation was 0.92% at six-months (n=53).
• Bulbar Function Scale (CNS-BFS) Sialorrhea Score [ Time Frame: Average between Screening Visit to Visit 3 ]
  The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the salivation (sialorrhea). There are 7 salivation (sialorrhea) questions, with a score range of 7 to 35.
• Bulbar Function Scale (CNS-BFS) Speech Score [ Time Frame: Average between Screening Visit to Visit 3 ]
  The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the speech. There are 7 speech questions, with a score range of 7 to 35.
• Bulbar Function Scale (CNS-BFS) Swallowing Score [ Time Frame: Average between Screening Visit to Visit 3 ]
  The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the swallowing. There are 7 swallowing questions, with a score range of 7 to 35.

Original Primary Outcome Measures (submitted: March 6, 2013)

Change in Center for Neurologic Study - Bulbar Function Scale (CNS-BFS) Score [ Time Frame: Screening Visit, Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]

The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. The scale was modeled on the Center for Neurologic Study Emotional Lability Scale (CNS-LS) that has been a robust endpoint in four clinical trials. The scale was validated in a large population of ALS patients (n=122) and detects impaired bulbar function at a sensitivity of 90% and a specificity of 0.97%. Test re-test correlation was 0.92% at six-months (n=53).

Current Secondary Outcome Measures (submitted: February 3, 2017)

• Center for Neurologic Study - Lability Scale (CNS-LS) Total Score [ Time Frame: Average between Screening Visit to Visit 3 ]
  The Center for Neurologic Study-Lability Scale (CNS-LS) is a 7-item self report scale that assesses pseudobulbar affect (PBA) by measuring the perceived frequency of PBA episodes (laughing or crying). Each item is scored using a 5-point Likert scale, from 1 (applies never) to 5 (applies most of the time). Scores range from 5-35. The higher the score, the worse the PBA.
• ALS Functional Rating Scale- Revised (ALSFRS-R) Total Score [ Time Frame: Average between Screening Visit to Visit 3 ]
  The ALSFRS-R is a quickly administered (5 min) ordinal rating scale used to determine a subject's assessment of their capability and independence in 12 functional activities. There are 12 questions, graded by the subject 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing.
• Visual Analog Scale - Speech Scores [ Time Frame: Average between Baseline Visit to Visit 3 ]
  Visual analog scales are useful for measuring complex clinical events and offer the advantage of self-administration and responsiveness to change over time. The scales designed for this study inventory three domains of bulbar function: speech, swallowing and salivation (sialorrhea). For each of these, subjects score themselves by indicating their level of function on a scale of 1 (severe impairment) to 10 (normal). Scores range from 1 to 10; the higher the score, the more normal the function.
• Ashworth Spasticity Scale Score - Right Arm [ Time Frame: Average between Baseline Visit to Visit 3 ]
  This is a standard measure for spasticity that has been used in numerous ALS clinical trials to assess spasticity due to upper motor neuron dysfunction in ALS. Data is generated from the clinical exam and scored from 1-5, the lowest score indicating normal tone and the highest muscle rigidity.
• Timed Reading of Test Paragraph Result [ Time Frame: Average between Baseline Visit to Visit 3 ]
  Subjects will be asked to read 'The Rainbow Passage' a commonly used test paragraph utilized by speech pathologists to assess speech rate (words/minute). Study staff will time the subject to determine how many words the subject reads per minute. It is used primarily because it contains every sound in the English language. Subjects will also be observed for loudness, nasality, and intelligibility.
• Average Water Swallowing Test (WST) [ Time Frame: Average between Baseline Visit to Visit 3 ]
  The Water Swallowing Test (WST) estimates swallowing speed, a useful and reproducible measure. While sitting, subjects are asked to drink 30 milliliters (mL) of liquid. The time for subjects to complete this task is a sensitive measure for the detection of swallowing dysfunction and is a simple measure for serial assessment of subjects. The test will be completed three times, with the best two scores recorded to obtain an average score. Following completion of the WST, the subject's swallowing abilities (choking, spillage, and effort) will be observed.
• Visual Analog Scale - Swallowing Score [ Time Frame: Average between Baseline Visit to Visit 3 ]
  Visual analog scales are useful for measuring complex clinical events and offer the advantage of self-administration and responsiveness to change over time. The scales designed for this study inventory three domains of bulbar function: speech, swallowing and salivation (sialorrhea). For each of these, subjects score themselves by indicating their level of function on a scale of 1 (severe impairment) to 10 (normal). Scores range from 1 to 10; the higher the score, the more normal the function.
• Visual Analog Scale - Salivation (Sialorrhea) Score [ Time Frame: Average between Baseline Visit to Visit 3 ]
  Visual analog scales are useful for measuring complex clinical events and offer the advantage of self-administration and responsiveness to change over time. The scales designed for this study inventory three domains of bulbar function: speech, swallowing and salivation (sialorrhea). For each of these, subjects score themselves by indicating their level of function on a scale of 1 (severe impairment) to 10 (normal). Scores range from 1 to 10; the higher the score, the more normal the function.
• Average Solids Swallowing Test [ Time Frame: Average between Baseline Visit to Visit 3 ]
  The Time Swallowing Test assesses the subject's ability to swallow solids. For this test, the subject will be asked to consume a tablespoon of cereal containing 5 cheerios. The subject will be instructed to close their mouth, chew and subsequently swallow the bolus. The time to complete this task will be recorded. The test will be completed three times to obtain an average score.
• Ashworth Spasticity Scale Score - Left Arm [ Time Frame: Average between Baseline Visit to Visit 3 ]
  This is a standard measure for spasticity that has been used in numerous ALS clinical trials to assess spasticity due to upper motor neuron dysfunction in ALS. Data is generated from the clinical exam and scored from 1-5, the lowest score indicating normal tone and the highest muscle rigidity.
• Ashworth Spasticity Scale Score - Right Leg [ Time Frame: Average between Baseline Visit to Visit 3 ]
  This is a standard measure for spasticity that has been used in numerous ALS clinical trials to assess spasticity due to upper motor neuron dysfunction in ALS. Data is generated from the clinical exam and scored from 1-5, the lowest score indicating normal tone and the highest muscle rigidity.
• Ashworth Spasticity Scale Score - Left Leg [ Time Frame: Average between Baseline Visit to Visit 3 ]
  This is a standard measure for spasticity that has been used in numerous ALS clinical trials to assess spasticity due to upper motor neuron dysfunction in ALS. Data is generated from the clinical exam and scored from 1-5, the lowest score indicating normal tone and the highest muscle rigidity.

Original Secondary Outcome Measures (submitted: March 6, 2013)

• Change in Center for Neurologic Study - Lability Scale (CNS-LS) Score [ Time Frame: Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]
  The Center for Neurologic Study-Lability Scale (CNS-LS) is a 7-item self report scale that assesses pseudobulbar affect (PBA) by measuring the perceived frequency of PBA episodes (laughing or crying).
• Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score [ Time Frame: Screening Visit, Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2), and a Telephone Call (28 + 5 days from Visit 3) ]
  The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival.
• Change in Slow Vital Capacity (SVC) Score [ Time Frame: Screening Visit, Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit) ]
  The vital capacity (VC) (percent of predicted normal) will be determined, using the slow VC method. The SVC can be measured using conventional spirometers that have had a calibration check prior to subject testing. A printout from the spirometer of all SVC trials will be retained.
• Change in Visual Analog Scale (Bulbar Function) Score [ Time Frame: Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]
  Visual analog scales are useful for measuring complex clinical events and offer the advantage of self-administration and responsiveness to change over time. The scales designed for this study inventory three domains of bulbar function: speech, swallowing and salivation. For each of these, subjects score themselves by indicating, on a scale of 1 to 10 (from normal to severe impairment), their level of function.
• Change in Ashworth Spasticity Scale Score [ Time Frame: Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]
  This is a standard measure for spasticity that has been used in numerous ALS clinical trials to assess spasticity due to upper motor neuron dysfunction in ALS. Data is generated from the clinical exam and scored from 1-5, the lowest score indicating normal tone and the highest muscle rigidity.
• Change in Timed Reading of Test Paragraph Result [ Time Frame: Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]
  Subjects will be asked to read 'The Rainbow Passage' a commonly used test paragraph utilized by speech pathologists to assess speech rate (words/minute). Study staff will time the subject to determine how many words the subject reads per minute. It is used primarily because it contains every sound in the English language. Subjects will also be observed for loudness, nasality, and intelligibility.
• Change in Water Swallowing Test (WST) Result [ Time Frame: Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]
  The Water Swallowing Test (WST) estimates swallowing speed, a useful and reproducible measure. While sitting, subjects are asked to drink 30 milliliters (mL) of liquid. The time for subjects to complete this task is a sensitive measure for the detection of swallowing dysfunction and is a simple measure for serial assessment of subjects. The test will be completed three times, with the best two scores recorded to obtain an average score. Following completion of the WST, the subject's swallowing abilities (choking, spillage, and effort) will be observed.
• Change in Timed Swallowing Test Result [ Time Frame: Baseline Visit, Visit 1 (28 ± 3 days from Baseline Visit), Visit 2 (10-15 days from Visit 1), and Visit 3 (28 ± 3 days from Visit 2) ]
  The Time Swallowing Test assesses the subject's ability to swallow solids. For this test, the subject will be asked to consume a tablespoon of cereal containing 5 cheerios. The subject will be instructed to close their mouth, chew and subsequently swallow the bolus. The time to complete this task will be recorded. The test will be completed three times to obtain an average score.

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

Descriptive Information

• Brief Title: Clinical Trial Nuedexta in Subjects With ALS
• Official Title: The Experimental Treatment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)
• Brief Summary: The purpose of this study is to determine whether Nuedexta is effective in the treatment of symptoms (impaired speech, swallowing, and saliva control)associated with Amyotrophic Lateral Sclerosis (ALS).

Detailed Description

Muscle weakness, the cardinal feature of ALS, leads to progressive loss of motor function affecting the limbs, tongue, respiratory and pharyngeal muscles. Symptomatic treatments such as the placement of a feeding tube, can compensate for the inability to swallow. Riluzole, the only approved treatment for ALS, may slow disease progression but no treatment is curative and none have improved function.

Unexpectedly, Nuedexta®, approved for the treatment of labile emotionality that occurs in association with ALS and other neurological disorders, has been observed to improve bulbar function, primarily speech and swallowing, in a number of neurological disorders, including ALS. The basis for this is conjectural but likely due to a direct effect of the drug on motor neurons in the part of the brain that controls speech and swallowing. The same part of the brain appears to modulate the expression of emotions and interestingly the site of action of the drug is the same as a site that has been implicated in a juvenile form of ALS.

This is a multicenter, randomized double-blind, placebo controlled, cross over study evaluating the palliative effect of Nuedexta® on bulbar dysfunction. It is expected that approximately 60 ALS patients from 7 clinical centers in the US will be enrolled.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis (ALS)

Intervention

• Drug: Nuedexta
  Nuedexta PO (by mouth) for 28 ± 3 days
  Other Name: dextromethorphan hydrobromide and quinidine sulfate
• Drug: Matching Placebo
  matching placebo PO (by mouth) for 28 ± 3 days
  Other Name: sugar pill

Study Arms

• Nuedexta then Matching Placebo
  Subjects in this arm will receive treatment with Nuedexta first for 28 days (±3 days) and then crossed over to receive treatment with matching placebo for 28 days (±3 days).
  Interventions:

  • Drug: Nuedexta
  • Drug: Matching Placebo
• Matching Placebo then Nuedexta
  Subjects in this arm will receive treatment with matching placebo first for 28 days (±3 days) and then crossed over to receive treatment with Nuedexta for 28 days (±3 days).
  Interventions:

  • Drug: Nuedexta
  • Drug: Matching Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 20, 2016): 90
• Original Estimated Enrollment (submitted: March 6, 2013): 60
• Actual Study Completion Date: March 2015
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria
• Age 18 years or older
• Exhibits bulbar dysfunction manifested by dysarthria and/or dysphagia, according to PI judgment, exhibits a score of 55 or above on the CNS-Bulbar Function Scale
• Capable of providing informed consent and following trial procedures
• Geographic accessibility to the site
• Women must not be able to become pregnant for the duration of the study and must be willing to be on two contraceptive therapies
• Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the screening visit
• Must be able to swallow capsules throughout the course of the study, according to PI judgment
• Subjects must not have taken riluzole for at least 30 days or be on a 50mg BID dose of riluzole for at least 30 days prior to randomization (subjects how have never taken riluzole are permitted in the study)
• Subjects taking anti-sialorrhea medication(s) must be on a stable dose for at least 30 days prior to randomization (anti-sialorrhea naïve subjects are permitted in the study)
• Must be able to safely swallow at least 30 milliliters (mLs) of water for the water swallowing test

Exclusion Criteria:

• Prior use of Nuedexta®
• Current use of dextromethorphan, quinidine, quinine, mefloquine or opioids
• History of quinidine, quinine, or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reactions
• History of known sensitivity or intolerability to dextromethorphan
• Use of an mono amine oxidase inhibitor (MAOI) or within 14 days of stopping an MAOI
• Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure
• Complete atrioventricular (AV) block without implanted pacemaker, or subjects at high risk of complete AV block
• Concomitant use with drugs that both prolong QT interval and are metabolized by cytochrome P 2D6 (CYP2D6) (i.e., thioridazine or pimozide)
• Exposure to any other experimental agent (off-label use or investigational) within 30 days prior to Baseline Visit
• Invasive ventilator dependence, such as tracheostomy
• Any history of either substance abuse within the past year, unstable psychiatric disease, cognitive impairment, or dementia, according to PI judgment
• Placement and/or usage of feeding tube
• Pregnant women or women currently breastfeeding
• Unable to turn diaphragm pacing device off during swallowing tests
• Salivatory Botox within 90 days (3 months) of screening
• Salivatory radiation within 180 days (6 months) of screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (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: NCT01806857
• Other Study ID Numbers: 2012P001274; 3FKVAD ( Other Grant/Funding Number: ALSA )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Richard A. Smith, MD, Center for Neurologic Study, La Jolla, California,
• Original Responsible Party: Same as current
• Current Study Sponsor: Center for Neurologic Study, La Jolla, California,
• Original Study Sponsor: Same as current

Collaborators

• ALS Association
• State University of New York - Upstate Medical University

Investigators

• Principal Investigator: Richard A Smith, MD; Center for Neurologic Study (CNS)
• Principal Investigator: Jeremy Shefner, MD, PhD; Barrow Neurological Institute
• Principal Investigator: Merit E Cudkowicz, MD, MSc; Massachusetts General Hospital (MGH)

• PRS Account: Center for Neurologic Study, La Jolla, California,
• Verification Date: February 2017