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Clinical Trial Nuedexta in Subjects With ALS

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01806857
First Posted: March 7, 2013
Last Update Posted: March 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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,
  Purpose
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).

Condition Intervention Phase
Amyotrophic Lateral Sclerosis (ALS) Drug: Nuedexta Drug: Matching Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The Experimental Treatment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)

Resource links provided by NLM:


Further study details as provided by Richard A. Smith, MD, Center for Neurologic Study, La Jolla, California,:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 90
Study Start Date: April 2013
Study Completion Date: March 2015
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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).
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
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).
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

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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): NCT01806857


Locations
United States, California
California Pacific Medical Center
San Francisco, California, United States, 94115
United States, District of Columbia
Georgetown University Medical Center
Washington D.C., District of Columbia, United States, 20007
United States, Michigan
Saint Mary's Health Care
Grand Rapids, Michigan, United States, 49503
United States, Minnesota
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
United States, Nebraska
Neurology Associates, P.C.
Lincoln, Nebraska, United States, 68506
United States, Ohio
The Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Oregon
Providence ALS Center
Portland, Oregon, United States, 97213
Sponsors and Collaborators
Center for Neurologic Study, La Jolla, California,
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)
  More Information

Additional Information:
Responsible Party: Richard A. Smith, MD, Director, Center for Neurologic Study, La Jolla, California,
ClinicalTrials.gov Identifier: NCT01806857     History of Changes
Other Study ID Numbers: 2012P001274
3FKVAD ( Other Grant/Funding Number: ALSA )
First Submitted: March 5, 2013
First Posted: March 7, 2013
Results First Submitted: August 9, 2016
Results First Posted: March 24, 2017
Last Update Posted: March 24, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Richard A. Smith, MD, Center for Neurologic Study, La Jolla, California,:
Amyotrophic lateral sclerosis
ALS
Nuedexta
Bulbar function
motor neurons

Additional relevant MeSH terms:
Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Dextromethorphan
Quinidine
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