Clinical Trial Nuedexta in Subjects With ALS

This study is currently recruiting participants.
Verified April 2014 by Center for Neurologic Study, La Jolla, California,
Sponsor:
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,
ClinicalTrials.gov Identifier:
NCT01806857
First received: March 5, 2013
Last updated: April 7, 2014
Last verified: April 2014
  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
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, 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 Center for Neurologic Study, La Jolla, California,:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 60
Study Start Date: April 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Nuedexta - 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
Matching Placebo - 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: Matching Placebo
matching placebo PO (by mouth) for 28 ± 3 days

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01806857

Contacts
Contact: Angela S Knox, MS, PMP 617-724-3314 aknox1@partners.org

Locations
United States, California
California Pacific Medical Center Recruiting
San Francisco, California, United States, 94115
Contact: Marguerite Engel    415-600-3758    engelm@cpmcri.org   
Contact: Dallas Forshew, RN, BSN    415-600-3928    forshed@cpmcri.org   
Principal Investigator: Jonathan Katz, MD         
United States, District of Columbia
Georgetown University Medical Center Recruiting
Washington D.C., District of Columbia, United States, 20007
Contact: Connell Owings, RN    202-444-2658    rco24@georgetown.edu   
Principal Investigator: Brent Harris, MD, PhD         
Principal Investigator: Michael Sirdofsky, MD         
United States, Michigan
Saint Mary's Health Care Recruiting
Grand Rapids, Michigan, United States, 49503
Contact: Lynn Cherney    616-685-5091    cherneyl@mercyhealth.com   
Principal Investigator: Herman Sullivan, MD         
United States, Minnesota
Hennepin County Medical Center Recruiting
Minneapolis, Minnesota, United States, 55415
Contact: Cindy Rohde, RN    612-873-2607    cindy.rohde@hcmed.org   
Principal Investigator: Gregg Meekins, MD         
United States, Nebraska
Neurology Associates, P.C. Recruiting
Lincoln, Nebraska, United States, 68506
Contact: Becky Weber, RN    402-483-5517    becky.weber70@gmail.com   
Principal Investigator: Gary Pattee, MD         
United States, Ohio
The Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Nicole Berry    216-445-1741    berryn@ccf.org   
Principal Investigator: Erik Pioro, MD, PhD         
United States, Oregon
Providence ALS Center Recruiting
Portland, Oregon, United States, 97213
Contact: Pamela Andrews, RN    503-962-1171    Pamela.Andrews@providence.org   
Principal Investigator: Kimberly Goslin, MD, PhD         
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 State University of New York - Upstate Medical University
Principal Investigator: Merit E Cudkowicz, MD, MSc Massachusetts General Hospital (MGH)
  More Information

Additional Information:
No publications provided

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
Study First Received: March 5, 2013
Last Updated: April 7, 2014
Health Authority: United States: Institutional Review Board

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

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

ClinicalTrials.gov processed this record on April 17, 2014