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

NCT00573443 | Completed Phase 3 Results DMC

• 1 other identifier: 07-AVR-123
• Study Type: interventional
• Target: 326
• Locations: 3 countries
• Sites: 62

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.

Conditions

Pseudobulbar Affect (PBA)

Keywords

Amyotrophic Lateral Sclerosis (Lou Gehrig's disease, ALS); Multiple Sclerosis (MS)

Outcome Measures

Primary Outcomes (1)

• PBA Episode Rate Ratio (Post/Pre), Regression Adjusted

  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 Outcomes (6)

• Mean Change From Baseline in CNS-LS Total Score by Visit

  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)

  Baseline to Day 84

• Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)

  Baseline to Day 84

• Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category

  Baseline and Day 84

• Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score

  Baseline and Day 84

Study Arms (3)

DM 30 mg/Q 10 mg

EXPERIMENTAL

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

DM 20 mg/ Q 10 mg

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks

Drug: Placebo

Interventions

dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg DRUG

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

Also known as: AVP-923, Nuedexta™, DM 20 mg/ Q 10 mg, DMQ

DM 20 mg/ Q 10 mg

dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg DRUG

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

Also known as: AVP-923, DM 30 mg/ Q 10 mg, DMQ

DM 30 mg/Q 10 mg

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.)

Sponsors & Collaborators

• Avanir Pharmaceuticals: lead
• Syneos Health: collaborator

Study Sites (62)

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

Location

Neuromuscular Research Center

Scottsdale, Arizona, 85258, United States

Location

South Coast Clinical Trials

Anaheim, California, 92804, United States

Location

UCI Medical Center

Irvine, California, 92868, United States

Location

Center for Neurologic Study

La Jolla, California, 92103, United States

Location

UCLA School of Medicine

Los Angeles, California, 90095, United States

Location

The Forbes Norris MDA/ALS Research Center - California Pacific Medical Center

San Francisco, California, 94115, United States

Location

The ALS Center at UCSF

San Francisco, California, 94117, United States

Location

University of Colorado at Denver & Health Science Center

Aurora, Colorado, 80045, United States

Location

Neuroscience Center

Fort Lauderdale, Florida, 33334, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Suncoast Neuroscience Associates

St. Petersburg, Florida, 33701, United States

Location

The ALS Center at Emory University

Atlanta, Georgia, 30322, United States

Location

Neurology Specialists of Decatur of Decatur

Decatur, Georgia, 30033, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Consultants in Neurology

Northbrook, Illinois, 60062, United States

Location

University of Kentucky Health Care - Dept. of Neurology

Lexington, Kentucky, 40536, United States

Location

The John Hopkins Universitiy

Baltimore, Maryland, 21287, United States

Location

Massachusets General Hospital

Boston, Massachusetts, 02129, United States

Location

Baystate Medical Center

Springfield, Massachusetts, 01199, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

St.Louis University - Neuromuscular Clinic

St Louis, Missouri, 63110, United States

Location

Advanced Neurology Specialists

Great Falls, Montana, 59405, United States

Location

Neurology Associates

Lincoln, Nebraska, 68506, United States

Location

Universitiy of Nevada

Las Vegas, Nevada, 89102, United States

Location

Upstate Clinical Research

Albany, New York, 12205, United States

Location

Jacobs Neurological Institute

Buffalo, New York, 14203, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Neurological Institute - Columbia Presbyterian Center

New York, New York, 10032, United States

Location

Carolinas Medical Center

Charlotte, North Carolina, 28207, United States

Location

Duke Universitiy Medical Center

Durham, North Carolina, 27710, United States

Location

Department of Neurology - The Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State Universitiy

Columbus, Ohio, 43210, United States

Location

Oregon Health Science University

Portland, Oregon, 97239, United States

Location

Drexel University - Department of Neurology

Philadelphia, Pennsylvania, 19107, United States

Location

The ALS Center - Penn Neurological Institute - The University of Pennsylvania

Philadelphia, Pennsylvania, 19107, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

The Methodist Hospital - Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Department of Neuropsychiatry - Texas Tech University

Lubbock, Texas, 79430, United States

Location

University of Texas Health Science Center

San Antonio, Texas, 78229, United States

Location

Universitiy of Vermont

Burlington, Vermont, 05405, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

Dean Foundation

Madison, Wisconsin, 53715, United States

Location

FACENE

Buenos Aires, Buenos Aires F.D., 1117ABD, Argentina

Location

IADIN

Buenos Aires, Buenos Aires F.D., C1055AAD, Argentina

Location

Hospital Italiano

Buenos Aires, Buenos Aires F.D., C1181ACH, Argentina

Location

INEBA

Buenos Aires, Buenos Aires F.D., C1192AAW, Argentina

Location

Hospital Ramos Mejia

Buenos Aires, Buenos Aires F.D., C1221ADC, Argentina

Location

Hospital Britanico

Buenos Aires, Buenos Aires F.D., C1280AEB, Argentina

Location

Policlinico Bancario

Buenos Aires, Buenos Aires F.D., C1416DRJ, Argentina

Location

FLENI

Buenos Aires, Buenos Aires F.D., C1428AQK, Argentina

Location

Hospital Militar Regional de Cordoba

Córdoba, Córdoba Province, X5000HGX, Argentina

Location

Instituto Medico Rodriguez Alfici

Godoy Cruz, Mendoza Province, M5501AAP, Argentina

Location

Instituto de Neurociencias Rosario

Rosario, Santa Fe Province, 2002KQJ, Argentina

Location

Santa Casa de Misericordia de Belo Horizonte

Belo Horizonte, M G, 30.150-221, Brazil

Location

Hospital de Clínicas-UFPR

Curitiba, Paraná, 80.060.900, Brazil

Location

Hospital da Restauração

Recife, Pernambuco, 52.010-040, Brazil

Location

Hospital Universitário Clementino Fraga Filho

Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil

Location

Hospital Moinhos de Vento

Porto Alegre, Rio Grande do Sul, 90.560.030, Brazil

Location

Hospital das Clínicas da Faculdade de Medicina da Universidade São Paulo

São Paulo, São Paulo, 05.403-000, Brazil

Location

Related Publications (1)

• 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.

  PMID: 20839238 RESULT

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Multiple Sclerosis

Interventions

Dextromethorphan; Quinidine; dextromethorphan - quinidine combination

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Cinchona Alkaloids; Quinuclidines; Quinolines; Heterocyclic Compounds, 2-Ring

Results Point of Contact

• Title: Nadine Knowles; Executive Director, Research & Development Operations
• Organization: Avanir Pharmaceuticals

nknowles@avanir.com

1-949-268-8972

Study Officials

• Adrian Hepner, M.D.

  Avanir Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 13, 2007
• First Posted: December 14, 2007
• Study Start: December 1, 2007
• Primary Completion: June 1, 2009
• Study Completion: September 1, 2009
• Last Updated: April 12, 2017
• Results First Posted: July 10, 2013

Record last verified: 2017-03

Locations

BR (6); US (45); AR (11)