Clinical trial NCT01806857: Clinical Trial Nuedexta in Subjects With ALS
Official title: The Experimental Treatment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis (ALS)
Keywords: Amyotrophic lateral sclerosis
ALS
Nuedexta
Bulbar function
motor neurons
Lead sponsor: Center for Neurologic Study, La Jolla, California,
Sponsor class: OTHER
Collaborators: name: ALS Association
name: State University of New York - Upstate Medical University
First posted: 2013-03-07
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Bulbar Function Scale (CNS-BFS) Total Score
timeFrame: Average between Screening Visit to Visit 3
measure: Bulbar Function Scale (CNS-BFS) Sialorrhea Score
timeFrame: Average between Screening Visit to Visit 3
measure: Bulbar Function Scale (CNS-BFS) Speech Score
timeFrame: Average between Screening Visit to Visit 3
measure: Bulbar Function Scale (CNS-BFS) Swallowing Score
timeFrame: Average between Screening Visit to Visit 3
Secondary outcomes:
measure: Center for Neurologic Study - Lability Scale (CNS-LS) Total Score
timeFrame: Average between Screening Visit to Visit 3
measure: ALS Functional Rating Scale- Revised (ALSFRS-R) Total Score
timeFrame: Average between Screening Visit to Visit 3
measure: Visual Analog Scale - Speech Scores
timeFrame: Average between Baseline Visit to Visit 3
measure: Ashworth Spasticity Scale Score - Right Arm
timeFrame: Average between Baseline Visit to Visit 3
measure: Timed Reading of Test Paragraph Result
timeFrame: Average between Baseline Visit to Visit 3
measure: Average Water Swallowing Test (WST)
timeFrame: Average between Baseline Visit to Visit 3
measure: Visual Analog Scale - Swallowing Score
timeFrame: Average between Baseline Visit to Visit 3
measure: Visual Analog Scale - Salivation (Sialorrhea) Score
timeFrame: Average between Baseline Visit to Visit 3
measure: Average Solids Swallowing Test
timeFrame: Average between Baseline Visit to Visit 3
measure: Ashworth Spasticity Scale Score - Left Arm
timeFrame: Average between Baseline Visit to Visit 3
measure: Ashworth Spasticity Scale Score - Right Leg
timeFrame: Average between Baseline Visit to Visit 3
measure: Ashworth Spasticity Scale Score - Left Leg
timeFrame: Average between Baseline Visit to Visit 3
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Washington D.C.
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Grand Rapids
country: United States
facility: Saint Mary's Health Care
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Lincoln
country: United States
facility: Neurology Associates, P.C.
state: Nebraska
city: Cleveland
country: United States
facility: The Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence ALS Center
state: Oregon
Study officials:
affiliation: Center for Neurologic Study (CNS)
name: Richard A Smith, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Barrow Neurological Institute
name: Jeremy Shefner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital (MGH)
name: Merit E Cudkowicz, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: