Clinical Trial Nuedexta in Subjects With ALS

Amyotrophic Lateral Sclerosis (ALS) Clinical Trial

Official title:

The Experimental Treatment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01806857
• Other study ID #: 2012P001274
• Secondary ID: 3FKVAD
• Status: Completed
• Phase: Phase 2
• First received: March 5, 2013
• Last updated: June 20, 2016
• Start date: April 2013
• Est. completion date: March 2015

Study information

• Verified date: June 2016
• Source: Center for Neurologic Study, La Jolla, California,
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Amyotrophic Lateral Sclerosis (ALS)
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Nuedexta
Nuedexta PO (by mouth) for 28 ± 3 days
• Matching Placebo
matching placebo PO (by mouth) for 28 ± 3 days

Locations

Country	Name	City	State
United States	The Cleveland Clinic	Cleveland	Ohio
United States	Saint Mary's Health Care	Grand Rapids	Michigan
United States	Neurology Associates, P.C.	Lincoln	Nebraska
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Providence ALS Center	Portland	Oregon
United States	California Pacific Medical Center	San Francisco	California
United States	Georgetown University Medical Center	Washington D.C.	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Center for Neurologic Study, La Jolla, California,	ALS Association, State University of New York - Upstate Medical University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Center for Neurologic Study - Bulbar Function Scale (CNS-BFS) Score	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).	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)	No
Secondary	Change in Center for Neurologic Study - Lability Scale (CNS-LS) Score	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).	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)	No
Secondary	Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score	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.	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)	No
Secondary	Change in Slow Vital Capacity (SVC) Score	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.	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)	No
Secondary	Change in Visual Analog Scale (Bulbar Function) Score	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.	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)	No
Secondary	Change in Ashworth Spasticity Scale Score	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.	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)	No
Secondary	Change in Timed Reading of Test Paragraph Result	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.	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)	No
Secondary	Change in Water Swallowing Test (WST) Result	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.	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)	No
Secondary	Change in Timed Swallowing Test Result	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.	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)	No

External Links

•   ALS Association Website
•   Northeast ALS Consortium Website