Clinical trial NCT00573443: Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS
Official title: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy and to Determine the Pharmacokinetics of Two Doses of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Pseudobulbar Affect (PBA) in Patients With Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pseudobulbar Affect (PBA)
Keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's disease, ALS)
Multiple Sclerosis (MS)
Lead sponsor: Avanir Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Syneos Health
First posted: 2007-12-14
Enrollment: 326
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Objectives of the study are to evaluate the safety, tolerability, and efficacy of two different doses of AVP-923 (capsules containing either 30 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate \[AVP-923-30\] or 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate \[AVP-923-20\]) when compared to placebo, for the treatment of PBA in a population of patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) over a 12-week period. An additional objective is to determine the pharmacokinetic parameters of the two different doses of AVP-923 in a subset of the study population.

Pseudobulbar Affect (PBA) is a condition characterized by involuntary, sudden and frequent episodes of laughing and/or crying out of proportion or incongruous to the underlying emotion of happiness or sadness Other terms used to describe this condition include emotional lability, emotionalism, emotional incontinence, emotional discontrol, excessive emotionalism, and pathological laughing and crying. The outbursts can occur spontaneously or in response to provocative stimuli such as questions or events.

A body of evidence suggests that PBA can be modulated through pharmacologic intervention.

Dextromethorphan (DM) is a low-affinity uncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, reducing the level of excitatory activity. DM also acts at the phencyclidine-binding site, which is part of the NMDA receptor complex. DM is a sigma receptor agonist, suppressing the release of excitatory neurotransmitters.

Quinidine (Q) is a known potent inhibitor of cytochrome P450 2D6 (CYP2D6), that decreases the metabolism of dextromethorphan and helps to achieve sustained and therapeutic levels of this drug.


Eligibility criteria: Main Inclusion Criteria:

* The patient has a diagnosis of Amyotrophic Lateral Sclerosis (according to El Escorial Criteria, WFN, 1998) and the time from diagnosis of ALS is not be longer than 30 months, or the patient has a diagnosis of multiple sclerosis or probable multiple sclerosis (according to McDonald criteria, 2001)
* The patient has a clinical history and clinical relevant symptoms of Pseudobulbar Affect (PBA)
* CNS-LS score at baseline is 13 or greater

Main Exclusion Criteria:

* Patients with myasthenia gravis
* Any personal history of complete heart block, QTc prolongation, or torsades de pointes
* Any family history of congenital QT interval prolongation syndrome
* Patients with known sensitivity to quinidine, dextromethorphan or opiate drugs (codeine, etc.)

Primary outcomes:
measure: PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
timeFrame: Baseline to Day 84
Secondary outcomes:
measure: Mean Change From Baseline in CNS-LS Total Score by Visit
timeFrame: Baseline, Day 15, Day 29, Day 57, Day 84
measure: Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population)
timeFrame: Baseline to Day 84
measure: Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)
timeFrame: Baseline to Day 84
measure: Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category
timeFrame: Baseline and Day 84
measure: Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score
timeFrame: Baseline and Day 84
measure: Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects
timeFrame: Baseline, Day 15, Day 29, Day 57, Day 84
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Scottsdale
country: United States
facility: Neuromuscular Research Center
state: Arizona
city: Anaheim
country: United States
facility: South Coast Clinical Trials
state: California
city: Irvine
country: United States
facility: UCI Medical Center
state: California
city: La Jolla
country: United States
facility: Center for Neurologic Study
state: California
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: San Francisco
country: United States
facility: The Forbes Norris MDA/ALS Research Center - California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: The ALS Center at UCSF
state: California
city: Aurora
country: United States
facility: University of Colorado at Denver & Health Science Center
state: Colorado
city: Ft. Lauderdale
country: United States
facility: Neuroscience Center
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: St. Petersburg
country: United States
facility: Suncoast Neuroscience Associates
state: Florida
city: Atlanta
country: United States
facility: The ALS Center at Emory University
state: Georgia
city: Decatur
country: United States
facility: Neurology Specialists of Decatur of Decatur
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Northbrook
country: United States
facility: Consultants in Neurology
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Health Care - Dept. of Neurology
state: Kentucky
city: Baltimore
country: United States
facility: The John Hopkins Universitiy
state: Maryland
city: Boston
country: United States
facility: Massachusets General Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: St. Louis
country: United States
facility: St.Louis University - Neuromuscular Clinic
state: Missouri
city: Great Falls
country: United States
facility: Advanced Neurology Specialists
state: Montana
city: Lincoln
country: United States
facility: Neurology Associates
state: Nebraska
city: Las Vegas
country: United States
facility: Universitiy of Nevada
state: Nevada
city: Albany
country: United States
facility: Upstate Clinical Research
state: New York
city: Buffalo
country: United States
facility: Jacobs Neurological Institute
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Neurological Institute - Columbia Presbyterian Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke Universitiy Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Department of Neurology - The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State Universitiy
state: Ohio
city: Portland
country: United States
facility: Oregon Health Science University
state: Oregon
city: Philadelphia
country: United States
facility: Drexel University - Department of Neurology
state: Pennsylvania
city: Philadelphia
country: United States
facility: The ALS Center - Penn Neurological Institute - The University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: The Methodist Hospital - Baylor College of Medicine
state: Texas
city: Lubbock
country: United States
facility: Department of Neuropsychiatry - Texas Tech University
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Burlington
country: United States
facility: Universitiy of Vermont
state: Vermont
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Madison
country: United States
facility: Dean Foundation
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: FACENE
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: IADIN
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Italiano
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: INEBA
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Ramos Mejia
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Britanico
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Policlinico Bancario
state: Ciudad de Buenos Aires
city: Buenos Aires
country: Argentina
facility: FLENI
state: Ciudad de Buenos Aires
city: Godoy Cruz
country: Argentina
facility: Instituto Medico Rodriguez Alfici
state: Mendoza
city: Rosario
country: Argentina
facility: Instituto de Neurociencias Rosario
state: Santa Fe
city: Cordoba
country: Argentina
facility: Hospital Militar Regional de Cordoba
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia de Belo Horizonte
state: M G
city: Recife
country: Brazil
facility: Hospital da Restauração
state: PE
city: Curitiba
country: Brazil
facility: Hospital de Clínicas-UFPR
state: PR
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitário Clementino Fraga Filho
state: RJ
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: RS
city: Sao Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidade São Paulo
state: SP
Study officials:
affiliation: Avanir Pharmaceuticals
name: Adrian Hepner, M.D.
role: STUDY_DIRECTOR
References:
citation: Pioro EP, Brooks BR, Cummings J, Schiffer R, Thisted RA, Wynn D, Hepner A, Kaye R; Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA Investigators. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010 Nov;68(5):693-702. doi: 10.1002/ana.22093.