Safety and Efficacy of AVP-923 in the Treatment of Central Neuropathic Pain in Multiple Sclerosis
- Conditions
- Central Neuropathic PainMultiple Sclerosis
- Interventions
- Registration Number
- NCT01324232
- Lead Sponsor
- Avanir Pharmaceuticals
- Brief Summary
The objectives of the study are to evaluate the safety, tolerability, and efficacy of 3 doses of AVP-923 capsules in the treatment of central neuropathic pain in participants with multiple sclerosis.
- Detailed Description
The objectives of the study are to evaluate the safety, tolerability, and efficacy of 3 doses of AVP-923 (dextromethorphan \[DM\]/quinidine \[Q\]) capsules containing either 45 mg DM and 10 mg Q (AVP-923-45) or 30 mg DM and 10 mg Q (AVP-923-30) or 20 mg DM and 10 mg Q (AVP-923-20) compared to placebo, for the treatment of central neuropathic pain in a population of participants with multiple sclerosis (MS) over a 12-week period. The MS participant population enrolled includes participants with relapsing-remitting multiple sclerosis (RRMS) and participants with secondary progressive multiple sclerosis (SPMS).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 209
Multiple Sclerosis (relapsing-remitting multiple sclerosis [RRMS] or secondary progressive multiple sclerosis [SPMS]), Clinical history and symptoms of central neuropathic pain (dysesthetic pain) for at least 3 months prior to screening, pain rating scale (PRS) baseline score = or > 4, No MS relapse within previous 30 days.
Main
Personal history of complete heart block, QT interval corrected for heart rate (QTc) prolongation, or torsades de pointes, family history of congenital QT interval prolongation syndrome, Myasthenia Gravis, Beck Depression Inventory Second Edition (BDI-II) score > 19
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo - AVP-923-45 AVP-923-45 - AVP-923-30 AVP-923-30 - AVP-923-20 AVP-923-20 -
- Primary Outcome Measures
Name Time Method Association Between the Dextromethorphan Plasma Concentration and the Change From Baseline Pain Rating Scale (PRS) Score to the Average Pain Rating Scale Score During Days 57 Through 84 Baseline; Days 57 through 84 (PRS score); Days 22 and 50 (dextromethorphan plasma concentrations) PRS required participants to rate their pain over the past 12 hours (hrs) on a scale of 0 to 10 (0=no pain; 10=worst possible pain). Baseline (B) PRS was defined as the average of the PRS scores in the last 7 days collected prior to the B visit. If participants did not have at least 4 PRS scores during the last 7 days prior to the B visit, then the average of up to 7 of the most recent PRS scores available prior to the B visit was used. Post-B PRS was the average of Days 57 through 84 values. For participants who did not have any PRS scores during Days 57 through 84, the average of the last 7 available post-B PRS scores was used. Change from B was calculated as the post-B score minus B score. The average logarithms of dextromethorphan plasma concentrations (Cmax) on Days 22 and 50 are reported in primary outcome measure #2 below. Pearson correlation was calculated between Cmax as one group of data across the reporting groups and Change from Baseline in PRS score.
Average Logarithms of Dextromethorphan (DM) Plasma Concentrations (Cmax) on Days 22 and 50 0 to 3 hours post-dose on Day 22 and 50 The average of the logarithms of the DM plasma concentrations on Days 22 and 50 were presented.
- Secondary Outcome Measures
Name Time Method Mean Change From Baseline in Fatigue Severity Scale (FSS) Scores at Days 57 Through 84 Baseline; Days 57 through 84 The FSS questionnaire consisted of 9 statements that attempted to explore the severity of fatigue symptoms in participants with MS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus, and was designed to differentiate fatigue from clinical depression because both share some of the same symptoms. Participants were asked to respond to each statement on a scale of 1 to 7, with 1 indicating "Strongly Disagree" and 7 indicating "Strongly Agree." Total score ranging from 9 to 63, was computed as the sum of the sub-scores for all 9 statements; a higher score indicated increasing fatigue. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Post-Baseline FSS score was the average of Day 57 through 84 values. The analysis was carried out using an ANCOVA model, with the FSS change from Baseline to Days 85 as the dependent variable,
Mean Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores at Day 85 Baseline; Day 85 MSIS-29, an instrument measuring the physical (20 items) and psychological (9 items) impact of MS from the participants' perspective was used to evaluate therapeutic effectiveness from the participants' perspective. Participants were asked to circle the response that best described the impact of MS on daily life on a scale of 0 (not at all) to 5 (extremely). The total MSIS-29 score ranged from 0 to 145, was calculated as the sum of the sub-scores for all 29 questions, with lower scores indicating better quality of life. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was carried out using an ANCOVA model, with the MSIS-29 score change from Baseline to Day 85 as the dependent variable, treatment group as a fixed effect, and the Baseline MSIS-29 as a covariate.
Comparison of the Adjusted Mean Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84 Baseline; Days 57 through 84 The PRS required participants to rate their pain over the past 12 hours on a scale of 0 to 10 (0=no pain; 10=worst possible pain) by circling the number that best described their pain on average over the past 12 hours. Baseline PRS was defined as the average of the PRS scores in the last 7 days collected prior to the Baseline visit. If participants did not have at least 4 PRS scores during the last 7 days prior to the Baseline visit, then the average of up to 7 of the most recent PRS scores available prior to the Baseline visit was used. Post-Baseline PRS was the average of the Day 57 through 84 values. For participants who did not have any PRS scores during Days 57 through 84, the average of the last 7 available post-Baseline PRS scores was used. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.
Mean Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at Days 22 and 85 Baseline; Days 22 and 85 The EDSS, a method of quantifying disability in participants with MS was based on neurological examination of 8 functional systems (FS) (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other) that allowed neurologists to assign a FS score to each of these systems. Neurological findings in each FS were scored on a scale of 0 (low level of problems) to 5 (high level of problems). The "other" category was not rated numerically but measured disability related to a particular issue, like motor loss. A total averaged EDSS score was then calculated on a scale of 0 (normal) to 10 (death from MS). The total EDSS score was determined by 2 factors: gait and FS scores. A higher score indicated greater disability. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Mean Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores at Day 85 Baseline; Day 85 PSQI, a self-rated questionnaire was used to assess sleep quality and disturbances over a 1-month time interval. A total of 19 individual items generated 7 component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component was scored from 0 (no difficulty) to 3 (severe difficulty). The sum of the scores for the 7 components yielded 1 global score (ranging from 0 to 21). Higher PSQI score indicated worse quality of sleep. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was carried out using an ANCOVA model, with the PSQI change from Baseline to Day 85 as the dependent variable, treatment group as a fixed effect, and the Baseline PQIS as a covariate.
Mean Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores at Day 85 Baseline; Day 85 MSNQ, a self-reporting, 15-item questionnaire was used to screen for cognitive impairment in participants with MS. Participants (or their informants) scored each item on a scale from 0 (not at all) to 4 (often and greatly interferes with life). The total MSNQ score was calculated as the sum of the sub-scores for all 15 questions and thus ranged from 0 to 60. A higher score indicated greater impairment. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was carried out using an ANCOVA model, with the MSNQ score change from Baseline to Day 85 as the dependent variable, treatment group as a fixed effect, and the Baseline MSNQ as a covariate.
Mean Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores at Day 85 Baseline; Day 85 The SDMT assessed organic cerebral dysfunction in both children (8 years and older) and adults. The SDMT involved a simple substitution task that normal participants could easily perform. Using a reference key, the examinee had 90 seconds to pair specific numbers with given geometric figures. The SDMT score was the total correct response (not counting errors) in 90 seconds and ranged from 0 to 110. Lower scores indicated increased dysfunction. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was carried out using an ANCOVA model, with the SDMT change from Baseline to Day 85 as the dependent variable, treatment group as a fixed effect, and the Baseline SDMT as a covariate.
Mean Change From Baseline in Beck Depression Inventory (BDI-II) Scores at Day 85 Baseline; Day 85 BDI-II, a 21-item, self-reported instrument was used to assess the existence and severity of symptoms of depression. Each item corresponded to a symptom of depression and as scored on a 4-point scale, ranging from 0 to 3. Participants were asked to consider each statement as it related to the way they have felt for the past 2 weeks. Each of the 21 items were summed to give a single score for the BDI-II (ranging from 0 to 63). A total score of 0 to 13 indicated minimal depression, a score of 14 to 19 indicated mild depression, a score of 20 to 28 indicated moderate depression, and a score of 29 to 63 indicated severe depression. Baseline was defined as last non-missing measurement prior to dosing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was carried out using an ANCOVA model, with the BDI-II change from Baseline to Day 85 as the dependent variable, treatment group as a fixed effect, and the Baseline BDI-II as a covariate.
Mean Overall Patient Global Impression of Change (PGIC) Scores at Day 85 Day 85 The PGIC was a standard, validated 7-point categorical scale. The participant was asked to assess the overall change in his or her central neuropathic pain symptoms since entry into the study on a scale of 0 to 7 (0=much better; 7=much worse). Higher scores indicated worsening.
Mean Numerical Rating Scale (NRS) Scores at Days 22, 50, and 85 Days 22, 50, and 85 The NRS was an 11-point scale for participant self-reporting of pain. The overall scores ranged from 0 (no spasticity) to 10 (worst possible spasticity). Higher scores indicated increased aggression.
Trial Locations
- Locations (71)
Coordinated Clinical Research
🇺🇸San Diego, California, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States
Rush-Presbyterian St. Luke's Medical Center
🇺🇸Chicago, Illinois, United States
Neurology Associates, PA
🇺🇸Maitland, Florida, United States
Shepard Center
🇺🇸Atlanta, Georgia, United States
St. Joseph's Hospital Medical Center
🇺🇸Phoenix, Arizona, United States
Advanced Neurology Specialists
🇺🇸Great Falls, Montana, United States
Neurological Associates
🇺🇸Henrico, Virginia, United States
Suncoast Neuroscience Associates, Inc.
🇺🇸Saint Petersburg, Florida, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Josephson Wallack Munshower Neurology, P.C.
🇺🇸Indianapolis, Indiana, United States
Laszlo J. Mate, MD
🇺🇸North Palm Beach, Florida, United States
Michigan Neurology Associates, P.C.
🇺🇸Clinton Township, Michigan, United States
University of Rochester
🇺🇸Rochester, New York, United States
Hospital Churruca-Visca
🇦🇷Buenos Aires, Argentina
Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
Hospital Univ. Nuestra Sra. De La Candelaria
🇪🇸Santa Cruz De Tenerife, Spain
Vseobecna fakultni nemocnice v Praze
🇨🇿Praha 2, Czechia
Niepubliczny Zaklad Opieki Zdrowotnej NEURO-MEDIC
🇵🇱Katowice, Poland
Hospital Universitari de Girona Dr. Josep Trueta
🇪🇸Girona, Cataluña, Spain
Hospital Universitario Vírgen Macarena
🇪🇸Sevilla, Spain
MidAmerica Neuroscience Institute
🇺🇸Lenexa, Kansas, United States
Hospital Britanico de Buenos Aires
🇦🇷Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
University of Colorado
🇺🇸Aurora, Colorado, United States
North Central Neurology Associates PC
🇺🇸Cullman, Alabama, United States
Neurology Associates of Ormond Beach
🇺🇸Ormond Beach, Florida, United States
Collier Neurologic Specialists
🇺🇸Naples, Florida, United States
Consultants in Neurology
🇺🇸Northbrook, Illinois, United States
NYU-Hospital for Joint Diseases
🇺🇸New York, New York, United States
Neurology Associates PC
🇺🇸Lincoln, Nebraska, United States
SUNY at Stony Brook
🇺🇸Stony Brook, New York, United States
Drexel University College of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
MS Center of Greater Washington
🇺🇸Vienna, Virginia, United States
Advanced Neurosciences Institute
🇺🇸Franklin, Tennessee, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Instituto de Neurologia Cognitiva
🇦🇷Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
Hospital Italiano
🇦🇷Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Instituto Argentino de Investigacion Neurologica
🇦🇷Ciudad de Buenos Aires, Buenos Aires, Argentina
Fakultni nemocnice u sv. Anny v Brne
🇨🇿Brno, Czechia
Medeos - Centro de Medicina Integral e Investigación Clínica
🇦🇷Ciudad Autonoma de Buenos Aires, Argentina
Instituto de Neurología y Neurorrehabilitación del Litoral
🇦🇷Santa Fe, Argentina
Nemocnice Jihlava, prispevkova organizace
🇨🇿Jihlava, Czechia
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Fakultni Nemocnice Ostrava
🇨🇿Ostrava, Czechia
Szpital Powiatowy w Czeladzi
🇵🇱Czeladz, Poland
Diagnomed Clinical Research Sp. z.o.o.
🇵🇱Katowice, Poland
Pomorskie Centrum Traumatologii im. M. Kopernika w Gdansku
🇵🇱Gdansk, Poland
Niepubliczny Zaklad Opieki Zdrowotnej PROFILAKTYKA
🇵🇱Katowice, Poland
Hospital del Mar
🇪🇸Barcelona, Cataluña, Spain
Neurologique Foundation
🇺🇸Ponte Vedra Beach, Florida, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Alta Bates Summit Medical Center
🇺🇸Berkeley, California, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
University of South Florida
🇺🇸Tampa, Florida, United States
Albany Medical Center Hospital
🇺🇸Albany, New York, United States
Wayne State University
🇺🇸Detroit, Michigan, United States
Oklahoma Medical Research Foundation
🇺🇸Oklahoma City, Oklahoma, United States
MultiCare Health System
🇺🇸Tacoma, Washington, United States
Geisinger Health System
🇺🇸Wilkes-Barre, Pennsylvania, United States
Hospital Vall D´Hebron
🇪🇸Barcelona, Cataluña, Spain
Fundación Argentina Contra las Enfermedades Neurológicas del Envejecimiento - FACENE
🇦🇷Buenos Aires, Argentina
Rocky Mountain MS Clinic
🇺🇸Salt Lake City, Utah, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Zespol Opieki Zdrowotnej w Konskich
🇵🇱Konskie, Poland
Specjalistyczny Gabinet Neurologiczny
🇵🇱Plewiska, Poland
Osrodek Badan Klinicznych Indywidualnej Specjalistycznej Praktyki Lekarskiej
🇵🇱Szczecin, Poland
Hospital Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Murcia, Spain
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
University of California, Irvine
🇺🇸Orange, California, United States
Niepubliczny Zaklad Opieki Zdrowotnej NEURO-KARD Ilkowski i Partnerzy Spolka Partnerska Lekarzy
🇵🇱Poznan, Poland
Geodyssey Research, LLC
🇺🇸Vero Beach, Florida, United States