Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS (STAR)

This study has been completed.
Sponsor:
Collaborator:
INC Research
Information provided by (Responsible Party):
Avanir Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00573443
First received: December 13, 2007
Last updated: June 5, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Pseudobulbar Affect (PBA)
Drug: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg
Drug: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Avanir Pharmaceuticals:

Primary Outcome Measures:
  • PBA Episode Rate Ratio (Post/Pre), Regression Adjusted [ Time Frame: Baseline to Day 84 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Mean Change From Baseline in CNS-LS Total Score by Visit [ Time Frame: Baseline, Day 15, Day 29, Day 57, Day 84 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population) [ Time Frame: Baseline to Day 84 ] [ Designated as safety issue: No ]
    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).

  • Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population) [ Time Frame: Baseline to Day 84 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score [ Time Frame: Baseline and Day 84 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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).


Enrollment: 326
Study Start Date: December 2007
Study Completion Date: September 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Drug: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg
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:
  • AVP-923
  • DM 30 mg/ Q 10 mg
  • DMQ
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
Drug: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg
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:
  • AVP-923
  • Nuedexta™
  • DM 20 mg/ Q 10 mg
  • DMQ
Placebo Comparator: Placebo
Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks
Drug: Placebo
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

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00573443

  Hide Study Locations
Locations
United States, Arizona
St. Joseph's Hospital and Medical Center
Phoenix, Arizona, United States, 85013
Neuromuscular Research Center
Scottsdale, Arizona, United States, 85258
United States, California
South Coast Clinical Trials
Anaheim, California, United States, 92804
UCI Medical Center
Irvine, California, United States, 92868
Center for Neurologic Study
La Jolla, California, United States, 92103
UCLA School of Medicine
Los Angeles, California, United States, 90095
The Forbes Norris MDA/ALS Research Center - California Pacific Medical Center
San Francisco, California, United States, 94115
The ALS Center at UCSF
San Francisco, California, United States, 94117
United States, Colorado
University of Colorado at Denver & Health Science Center
Aurora, Colorado, United States, 80045
United States, Florida
Neuroscience Center
Ft. Lauderdale, Florida, United States, 33334
Mayo Clinic
Jacksonville, Florida, United States, 32224
University of Miami
Miami, Florida, United States, 33136
Suncoast Neuroscience Associates
St. Petersburg, Florida, United States, 33701
United States, Georgia
The ALS Center at Emory University
Atlanta, Georgia, United States, 30322
Neurology Specialists of Decatur of Decatur
Decatur, Georgia, United States, 30033
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Consultants in Neurology
Northbrook, Illinois, United States, 60062
United States, Kentucky
University of Kentucky Health Care - Dept. of Neurology
Lexington, Kentucky, United States, 40536
United States, Maryland
The John Hopkins Universitiy
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusets General Hospital
Boston, Massachusetts, United States, 02129
Baystate Medical Center
Springfield, Massachusetts, United States, 01199
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, Missouri
St.Louis University - Neuromuscular Clinic
St. Louis, Missouri, United States, 63110
United States, Montana
Advanced Neurology Specialists
Great Falls, Montana, United States, 59405
United States, Nebraska
Neurology Associates
Lincoln, Nebraska, United States, 68506
United States, Nevada
Universitiy of Nevada
Las Vegas, Nevada, United States, 89102
United States, New York
Upstate Clinical Research
Albany, New York, United States, 12205
Jacobs Neurological Institute
Buffalo, New York, United States, 14203
Mount Sinai Medical Center
New York, New York, United States, 10029
Neurological Institute - Columbia Presbyterian Center
New York, New York, United States, 10032
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States, 28207
Duke Universitiy Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Department of Neurology - The Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Ohio State Universitiy
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Health Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
The ALS Center - Penn Neurological Institute - The University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19107
Drexel University - Department of Neurology
Philadelphia, Pennsylvania, United States, 19107
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
The Methodist Hospital - Baylor College of Medicine
Houston, Texas, United States, 77030
Department of Neuropsychiatry - Texas Tech University
Lubbock, Texas, United States, 79430
University of Texas Health Science Center
San Antonio, Texas, United States, 78229
United States, Vermont
Universitiy of Vermont
Burlington, Vermont, United States, 05405
United States, West Virginia
West Virginia University
Morgantown, West Virginia, United States, 26506
United States, Wisconsin
Dean Foundation
Madison, Wisconsin, United States, 53715
Argentina
Policlinico Bancario
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1416DRJ
Hospital Britanico
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1280AEB
Hospital Italiano
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1181ACH
INEBA
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1192AAW
IADIN
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1055AAD
Hospital Ramos Mejia
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1221ADC
FLENI
Buenos Aires, Ciudad de Buenos Aires, Argentina, C1428AQK
FACENE
Buenos Aires, Ciudad de Buenos Aires, Argentina, 1117ABD
Instituto Medico Rodriguez Alfici
Godoy Cruz, Mendoza, Argentina, M5501AAP
Instituto de Neurociencias Rosario
Rosario, Santa Fe, Argentina, 2002KQJ
Hospital Militar Regional de Cordoba
Cordoba, Argentina, X5000HGX
Brazil
Santa Casa de Misericordia de Belo Horizonte
Belo Horizonte, M G, Brazil, 30.150-221
Hospital da Restauração
Recife, PE, Brazil, 52.010-040
Hospital de Clínicas-UFPR
Curitiba, PR, Brazil, 80.060.900
Hospital Universitário Clementino Fraga Filho
Rio de Janeiro, RJ, Brazil, 21941-913
Hospital Moinhos de Vento
Porto Alegre, RS, Brazil, 90.560.030
Hospital das Clínicas da Faculdade de Medicina da Universidade São Paulo
Sao Paulo, SP, Brazil, 05.403-000
Sponsors and Collaborators
Avanir Pharmaceuticals
INC Research
Investigators
Study Director: Adrian Hepner, M.D. Avanir Pharmaceuticals
  More Information

Publications:
Responsible Party: Avanir Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00573443     History of Changes
Other Study ID Numbers: 07-AVR-123
Study First Received: December 13, 2007
Results First Received: July 18, 2011
Last Updated: June 5, 2013
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Argentina: Human Research Bioethics Committee
Brazil: Ministry of Health
Brazil: National Committee of Ethics in Research

Keywords provided by Avanir Pharmaceuticals:
Amyotrophic Lateral Sclerosis (Lou Gehrig's disease, ALS)
Multiple Sclerosis (MS)

Additional relevant MeSH terms:
Amyotrophic Lateral Sclerosis
Multiple Sclerosis
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Central Nervous System Diseases
Demyelinating Autoimmune Diseases, CNS
Demyelinating Diseases
Immune System Diseases
Metabolic Diseases
Motor Neuron Disease
Nervous System Diseases
Neurodegenerative Diseases
Neuromuscular Diseases
Proteostasis Deficiencies
Spinal Cord Diseases
TDP-43 Proteinopathies
Dextromethorphan
Quinidine
Quinidine gluconate
Adrenergic Agents
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Anti-Arrhythmia Agents
Anti-Infective Agents
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Antitussive Agents
Cardiovascular Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on October 29, 2014