- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00573443
Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS (STAR)
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)
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.
Study Overview
Status
Conditions
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Cordoba, Argentina, X5000HGX
- Hospital Militar Regional de Cordoba
-
-
Ciudad de Buenos Aires
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, 1117ABD
- FACENE
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1055AAD
- IADIN
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1181ACH
- Hospital Italiano
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1192AAW
- INEBA
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1221ADC
- Hospital Ramos Mejia
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1280AEB
- Hospital Británico
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1416DRJ
- Policlinico Bancario
-
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1428AQK
- FLENI
-
-
Mendoza
-
Godoy Cruz, Mendoza, Argentina, M5501AAP
- Instituto Médico Rodriguez Alfici
-
-
Santa Fe
-
Rosario, Santa Fe, Argentina, 2002KQJ
- Instituto de Neurociencias Rosario
-
-
-
-
M G
-
Belo Horizonte, M G, Brazil, 30.150-221
- Santa Casa de Misericordia de Belo Horizonte
-
-
PE
-
Recife, PE, Brazil, 52.010-040
- Hospital da Restauração
-
-
PR
-
Curitiba, PR, Brazil, 80.060.900
- Hospital de Clínicas-UFPR
-
-
RJ
-
Rio de Janeiro, RJ, Brazil, 21941-913
- Hospital Universitario Clementino Fraga Filho
-
-
RS
-
Porto Alegre, RS, Brazil, 90.560.030
- Hospital Moinhos de Vento
-
-
SP
-
Sao Paulo, SP, Brazil, 05.403-000
- Hospital das Clínicas da Faculdade de Medicina da Universidade São Paulo
-
-
-
-
Arizona
-
Phoenix, Arizona, United States, 85013
- St. Joseph's Hospital and Medical Center
-
Scottsdale, Arizona, United States, 85258
- Neuromuscular Research Center
-
-
California
-
Anaheim, California, United States, 92804
- South Coast Clinical Trials
-
Irvine, California, United States, 92868
- UCI Medical Center
-
La Jolla, California, United States, 92103
- Center for Neurologic Study
-
Los Angeles, California, United States, 90095
- UCLA School of Medicine
-
San Francisco, California, United States, 94115
- The Forbes Norris MDA/ALS Research Center - California Pacific Medical Center
-
San Francisco, California, United States, 94117
- The ALS Center at UCSF
-
-
Colorado
-
Aurora, Colorado, United States, 80045
- University of Colorado at Denver & Health Science Center
-
-
Florida
-
Ft. Lauderdale, Florida, United States, 33334
- Neuroscience Center
-
Jacksonville, Florida, United States, 32224
- Mayo Clinic
-
Miami, Florida, United States, 33136
- University of Miami
-
St. Petersburg, Florida, United States, 33701
- Suncoast Neuroscience Associates
-
-
Georgia
-
Atlanta, Georgia, United States, 30322
- The ALS Center at Emory University
-
Decatur, Georgia, United States, 30033
- Neurology Specialists of Decatur of Decatur
-
-
Illinois
-
Chicago, Illinois, United States, 60611
- Northwestern University
-
Northbrook, Illinois, United States, 60062
- Consultants in Neurology
-
-
Kentucky
-
Lexington, Kentucky, United States, 40536
- University of Kentucky Health Care - Dept. of Neurology
-
-
Maryland
-
Baltimore, Maryland, United States, 21287
- The John Hopkins Universitiy
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02129
- Massachusets General Hospital
-
Springfield, Massachusetts, United States, 01199
- Baystate Medical Center
-
-
Michigan
-
Ann Arbor, Michigan, United States, 48109
- University of Michigan
-
Detroit, Michigan, United States, 48202
- Henry Ford Hospital
-
-
Missouri
-
St. Louis, Missouri, United States, 63110
- St.Louis University - Neuromuscular Clinic
-
-
Montana
-
Great Falls, Montana, United States, 59405
- Advanced Neurology Specialists
-
-
Nebraska
-
Lincoln, Nebraska, United States, 68506
- Neurology Associates
-
-
Nevada
-
Las Vegas, Nevada, United States, 89102
- Universitiy of Nevada
-
-
New York
-
Albany, New York, United States, 12205
- Upstate Clinical Research
-
Buffalo, New York, United States, 14203
- Jacobs Neurological Institute
-
New York, New York, United States, 10029
- Mount Sinai Medical Center
-
New York, New York, United States, 10032
- Neurological Institute - Columbia Presbyterian Center
-
-
North Carolina
-
Charlotte, North Carolina, United States, 28207
- Carolinas Medical Center
-
Durham, North Carolina, United States, 27710
- Duke Universitiy Medical Center
-
-
Ohio
-
Cleveland, Ohio, United States, 44195
- Department of Neurology - The Cleveland Clinic Foundation
-
Columbus, Ohio, United States, 43210
- Ohio State Universitiy
-
-
Oregon
-
Portland, Oregon, United States, 97239
- Oregon Health Science University
-
-
Pennsylvania
-
Philadelphia, Pennsylvania, United States, 19107
- Drexel University - Department of Neurology
-
Philadelphia, Pennsylvania, United States, 19107
- The ALS Center - Penn Neurological Institute - The University of Pennsylvania
-
-
Tennessee
-
Nashville, Tennessee, United States, 37232
- Vanderbilt University
-
-
Texas
-
Houston, Texas, United States, 77030
- The Methodist Hospital - Baylor College of Medicine
-
Lubbock, Texas, United States, 79430
- Department of Neuropsychiatry - Texas Tech University
-
San Antonio, Texas, United States, 78229
- University of Texas Health Science Center
-
-
Vermont
-
Burlington, Vermont, United States, 05405
- Universitiy of Vermont
-
-
West Virginia
-
Morgantown, West Virginia, United States, 26506
- West Virginia University
-
-
Wisconsin
-
Madison, Wisconsin, United States, 53715
- Dean Foundation
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: DM 30 mg/Q 10 mg
AVP-923-30/10 Capsules (30 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks
|
Dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) capsules (AVP-923 capsules), containing DM 30 mg/ Q 10 mg taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period
Other Names:
|
Experimental: DM 20 mg/ Q 10 mg
AVP-923-20/10 Capsules (20 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks
|
Dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) capsules (AVP-923 capsules), containing DM 20 mg/ Q 10 mg, taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period
Other Names:
|
Placebo Comparator: Placebo
Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks
|
Placebo capsules (identical in appearance to AVP-923 capsules being studied in this trial), taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
Time Frame: Baseline to Day 84
|
Episodes were counted each day and recorded in a daily diary.
The outcome measure is the ratio of the episode rate over the 84-day treatment period to the rate during the baseline period, adjusted for study site, and underlying disease using longitudinal negative binomial regression.
|
Baseline to Day 84
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Mean Change From Baseline in CNS-LS Total Score by Visit
Time Frame: Baseline, Day 15, Day 29, Day 57, Day 84
|
Center for Neurologic Studies-Lability Scale (CNS-LS) is an instrument for the measurement of PBA that has been validated for the use in patients with ALS and MS.
It is a 7-item self-report questionnaire that measures the frequency and severity of PBA episodes, including assessments of labile laughter and labile tearfulness,and provides a score for total PBA (total score can range from 7-35).
The following 5-point scoring was used: 1=Applies never, 2=Applies rarely, 3=Applies occasionally, 4=Applies frequently, 5=Applies most of the time.
A score of 13 or higher may suggest PBA, and the higher the score the more severe the episodes.
|
Baseline, Day 15, Day 29, Day 57, Day 84
|
Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population)
Time Frame: Baseline to Day 84
|
The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains.
The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe).
The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities.
The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
|
Baseline to Day 84
|
Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)
Time Frame: Baseline to Day 84
|
The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains.
The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe).
The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities.
The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
|
Baseline to Day 84
|
Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category
Time Frame: Baseline and Day 84
|
The SF-36 is designed to examine a person's perceived health status.
The SF-36 includes one multi-item scale measuring eight health concepts: vitality, physical functioning, bodily pain, general health perceptions, physical role-, emotional role-, social role functioning, and mental health.
Answers to each question are scored and summed to produce raw scale scores for each health concept which are then transformed to a 0 - 100 scale, a high score defining a more favorable health state.
An aggregate summary measure is calculated by averaging the scores from the eight health concepts.
|
Baseline and Day 84
|
Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score
Time Frame: Baseline and Day 84
|
The BDI-II is a 21-item self report instrument intended to assess the existence and severity of symptoms of depression, summed to give a single score.
The BDI-II uses a 4-point for each item ranging from 0 to 3. A total score of 0-13 is considered minimal range, 14 to 19 is mild, 20 to 28 is moderate, and 29 to 63 is severe.
|
Baseline and Day 84
|
Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects
Time Frame: Baseline, Day 15, Day 29, Day 57, Day 84
|
Subjects with MS were instructed to also record daily the pain they experienced using the PRS.
After evaluating the subject's ability to comply with these requirements, the investigator determined if a caregiver should complete the study diary and assessments.
Subjects rated their pain over the past 12 hours on a scale of 0 to 10 (0=none, 10=worst pain ever experienced).
|
Baseline, Day 15, Day 29, Day 57, Day 84
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Adrian Hepner, M.D., Avanir Pharmaceuticals
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Metabolic Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Spinal Cord Diseases
- TDP-43 Proteinopathies
- Proteostasis Deficiencies
- Motor Neuron Disease
- Amyotrophic Lateral Sclerosis
- Physiological Effects of Drugs
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Anti-Infective Agents
- Muscarinic Antagonists
- Cholinergic Antagonists
- Cholinergic Agents
- Enzyme Inhibitors
- Excitatory Amino Acid Antagonists
- Excitatory Amino Acid Agents
- Membrane Transport Modulators
- Cytochrome P-450 Enzyme Inhibitors
- Voltage-Gated Sodium Channel Blockers
- Sodium Channel Blockers
- Cytochrome P-450 CYP2D6 Inhibitors
- Respiratory System Agents
- Antiprotozoal Agents
- Antiparasitic Agents
- Antimalarials
- Antitussive Agents
- Adrenergic alpha-Antagonists
- Dextromethorphan
- Quinidine
- Quinidine gluconate
Other Study ID Numbers
- 07-AVR-123
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Pseudobulbar Affect (PBA)
-
St. Joseph's Hospital and Medical Center, PhoenixAvanir PharmaceuticalsTerminatedAlzheimer's Disease | Pseudobulbar Affect (PBA)United States
-
Avanir PharmaceuticalsTerminatedPseudobulbar Affect (Involuntary Laughing and/or Crying)United States
-
Avanir PharmaceuticalsCompletedStroke | Dementia | Traumatic Brain Injury (TBI) | Pseudobulbar Affect (PBA)United States
-
Grupo LusófonaCompleted
-
Universitaet InnsbruckParacelsus Medical UniversityCompleted
-
University of ReadingWild Blueberry Association of North America (WBANA)CompletedMood | Cognition | AffectUnited Kingdom
-
University of Maryland, BaltimoreCompleted
-
Unilever R&DLiverpool John Moores UniversityCompletedCerebrovascular Circulation | AffectUnited Kingdom
-
Northumbria UniversityProcter and GambleCompletedCognitive Change | Affect
Clinical Trials on dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg
-
Vigonvita Life SciencesCompleted
-
Cerevel Therapeutics, LLCRecruitingSchizophreniaUnited States, Bulgaria
-
Taisho Pharmaceutical Co., Ltd.Completed
-
ShireCompleted
-
Jiangsu Alphamab Biopharmaceuticals Co., LtdCompletedGastric/Gastroesophageal Junction CancerChina
-
GlaxoSmithKlineCompleted
-
MedImmune LLCCompletedHealthy VolunteerUnited Kingdom
-
TaiRx, Inc.Recruiting
-
H. Lundbeck A/STerminatedHealthy | Parkinson DiseaseFrance
-
Otsuka Pharmaceutical Development & Commercialization...Bill and Melinda Gates FoundationCompletedPulmonary TBSouth Africa