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

Pseudobulbar Affect (PBA) Clinical Trial

— STAR  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00573443
• Other study ID #: 07-AVR-123
• Status: Completed
• Phase: Phase 3
• First received: December 13, 2007
• Last updated: June 5, 2013
• Start date: December 2007
• Est. completion date: September 2009

Study information

• Verified date: June 2013
• Source: Avanir Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaArgentina: Human Research Bioethics CommitteeBrazil: Ministry of HealthBrazil: National Committee of Ethics in Research
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 326
• Est. completion date: September 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Multiple Sclerosis
• Pseudobulbar Affect (PBA)

Intervention

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
• 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
• 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

Locations

Country	Name	City	State
Argentina	FACENE	Buenos Aires	Ciudad de Buenos Aires
Argentina	FLENI	Buenos Aires	Ciudad de Buenos Aires
Argentina	Hospital Britanico	Buenos Aires	Ciudad de Buenos Aires
Argentina	Hospital Italiano	Buenos Aires	Ciudad de Buenos Aires
Argentina	Hospital Ramos Mejia	Buenos Aires	Ciudad de Buenos Aires
Argentina	IADIN	Buenos Aires	Ciudad de Buenos Aires
Argentina	INEBA	Buenos Aires	Ciudad de Buenos Aires
Argentina	Policlinico Bancario	Buenos Aires	Ciudad de Buenos Aires
Argentina	Hospital Militar Regional de Cordoba	Cordoba
Argentina	Instituto Medico Rodriguez Alfici	Godoy Cruz	Mendoza
Argentina	Instituto de Neurociencias Rosario	Rosario	Santa Fe
Brazil	Santa Casa de Misericordia de Belo Horizonte	Belo Horizonte	M G
Brazil	Hospital de Clínicas-UFPR	Curitiba	PR
Brazil	Hospital Moinhos de Vento	Porto Alegre	RS
Brazil	Hospital da Restauração	Recife	PE
Brazil	Hospital Universitário Clementino Fraga Filho	Rio de Janeiro	RJ
Brazil	Hospital das Clínicas da Faculdade de Medicina da Universidade São Paulo	Sao Paulo	SP
United States	Upstate Clinical Research	Albany	New York
United States	South Coast Clinical Trials	Anaheim	California
United States	University of Michigan	Ann Arbor	Michigan
United States	The ALS Center at Emory University	Atlanta	Georgia
United States	University of Colorado at Denver & Health Science Center	Aurora	Colorado
United States	The John Hopkins Universitiy	Baltimore	Maryland
United States	Massachusets General Hospital	Boston	Massachusetts
United States	Jacobs Neurological Institute	Buffalo	New York
United States	Universitiy of Vermont	Burlington	Vermont
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Department of Neurology - The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State Universitiy	Columbus	Ohio
United States	Neurology Specialists of Decatur of Decatur	Decatur	Georgia
United States	Henry Ford Hospital	Detroit	Michigan
United States	Duke Universitiy Medical Center	Durham	North Carolina
United States	Neuroscience Center	Ft. Lauderdale	Florida
United States	Advanced Neurology Specialists	Great Falls	Montana
United States	The Methodist Hospital - Baylor College of Medicine	Houston	Texas
United States	UCI Medical Center	Irvine	California
United States	Mayo Clinic	Jacksonville	Florida
United States	Center for Neurologic Study	La Jolla	California
United States	Universitiy of Nevada	Las Vegas	Nevada
United States	University of Kentucky Health Care - Dept. of Neurology	Lexington	Kentucky
United States	Neurology Associates	Lincoln	Nebraska
United States	UCLA School of Medicine	Los Angeles	California
United States	Department of Neuropsychiatry - Texas Tech University	Lubbock	Texas
United States	Dean Foundation	Madison	Wisconsin
United States	University of Miami	Miami	Florida
United States	West Virginia University	Morgantown	West Virginia
United States	Vanderbilt University	Nashville	Tennessee
United States	Mount Sinai Medical Center	New York	New York
United States	Neurological Institute - Columbia Presbyterian Center	New York	New York
United States	Consultants in Neurology	Northbrook	Illinois
United States	Drexel University - Department of Neurology	Philadelphia	Pennsylvania
United States	The ALS Center - Penn Neurological Institute - The University of Pennsylvania	Philadelphia	Pennsylvania
United States	St. Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Oregon Health Science University	Portland	Oregon
United States	University of Texas Health Science Center	San Antonio	Texas
United States	The ALS Center at UCSF	San Francisco	California
United States	The Forbes Norris MDA/ALS Research Center - California Pacific Medical Center	San Francisco	California
United States	Neuromuscular Research Center	Scottsdale	Arizona
United States	Baystate Medical Center	Springfield	Massachusetts
United States	St.Louis University - Neuromuscular Clinic	St. Louis	Missouri
United States	Suncoast Neuroscience Associates	St. Petersburg	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Avanir Pharmaceuticals	INC Research

Countries where clinical trial is conducted

United States,  Argentina,  Brazil, 

References & 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. 20 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Mean Change From Baseline in CNS-LS Total Score by Visit	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	No
Secondary	Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population)	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	No
Secondary	Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)	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	No
Secondary	Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category	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	No
Secondary	Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score	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	No
Secondary	Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects	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	No