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

March 15, 2017 updated by: Avanir Pharmaceuticals

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

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

326

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
      • 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
  • Brazil
    • 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
  • United States
    • 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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
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
  • DMQ
  • DM 30 mg/ Q 10 mg
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

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

This is where you will find people and organizations involved with this study.

Sponsor

Avanir Pharmaceuticals

Collaborators

Syneos Health

Investigators

  • Study Director: Adrian Hepner, M.D., Avanir Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2007

Primary Completion (Actual)

June 1, 2009

Study Completion (Actual)

September 1, 2009

Study Registration Dates

First Submitted

December 13, 2007

First Submitted That Met QC Criteria

December 13, 2007

First Posted (Estimate)

December 14, 2007

Study Record Updates

Last Update Posted (Actual)

April 12, 2017

Last Update Submitted That Met QC Criteria

March 15, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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.

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