Randomized, Controlled Trial of
`Dextromethorphan/Quinidine for
`Pseudobulbar Affect in Multiple Sclerosis
`
`Hillel S. Panitch, MD,1 Ronald A. Thisted, PhD,2 Richard A. Smith, MD,3 Daniel R. Wynn, MD,4
`James P. Wymer, MD, PhD,5 Anat Achiron, MD, PhD,6 Timothy L. Vollmer, MD,7 Raul N. Mandler, MD,8
`Dennis W. Dietrich, MD,9 Malcolm Fletcher, LRCP, MRCS,10 Laura E. Pope, PhD,11 James E. Berg, BA,11
`and Ariel Miller, MD, PhD,12 for the Pseudobulbar Affect in Multiple Sclerosis Study Group
`
`Objective: To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) com-
`pared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients.
`Methods: A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with
`the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between
`visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale.
`Results: Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving
`placebo (p ⬍ 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the
`number of crying or laughing episodes (p ⱕ 0.0077), quality of life (p ⬍ 0.0001), quality of relationships (p ⫽ 0.0001), and pain
`intensity score (p ⫽ 0.0271). DM/Q was well tolerated; only dizziness occurred with greater frequency than with placebo.
`Interpretation: Results in multiple sclerosis patients were similar to those of a previous study in amyotrophic lateral sclerosis,
`demonstrating that DM/Q may be beneficial in treating potentially disabling pseudobulbar affect in a variety of neurological
`disorders.
`
`Ann Neurol 2006;59:780 –787
`
`Pseudobulbar affect (PBA), also known as emotional
`lability, is characterized by frequent and inappropriate
`episodes of crying, laughing, or both and is associated
`with neurological disorders such as stroke, amyotrophic
`lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s
`disease, and traumatic brain injury. It occurs in ap-
`proximately 10% of patients with multiple sclerosis
`(MS).1 The cause of PBA is unknown, but recent evi-
`dence implicates the disruption of neural pathways em-
`anating from the brainstem and cerebellum that nor-
`mally control the expression of emotions.2 Although
`tricyclic antidepressants, selective serotonin reuptake
`inhibitors, and L-dopa are sometimes used to treat
`PBA,3– 6 no drug has been rigorously studied or ap-
`proved for this purpose.
`Dextromethorphan (DM), the dextrorotatory analogue
`
`of levorphanol, is a ␴-1 receptor agonist, suppressing the
`release of excitatory neurotransmitters,7 and is an uncom-
`the N-methyl-D-aspartate–sensi-
`petitive antagonist of
`tive8,9 ionotropic glutamate receptor. The potential for
`useful pharmacology is limited, however, because DM is
`extensively metabolized by cytochrome P450 2D6 to dex-
`trorphan (DX), which is rapidly glucuronidated10 and un-
`able to cross the blood–brain barrier.11
`Quinidine (Q) is one of the most potent inhibitors
`of cytochrome P450 2D6 activity.12 Concomitant dos-
`ing with Q at doses 10- to 20-fold lower than antiar-
`rhythmic doses increases and sustains the concentration
`of DM in plasma, and thereby enhances its potential
`for therapeutic efficacy.13
`A study conducted to test the hypothesis that the an-
`tiglutamate excitatory properties of DM/Q would be
`
`From the 1Neurology Health Care Service, Fletcher Allen Health Care,
`University of Vermont, Burlington, VT; 2Department of Health Stud-
`ies, The University of Chicago, Chicago, IL; 3Center for Neurologic
`Study, La Jolla, CA; 4Consultants in Neurology LTD, Northbrook, IL;
`5Upstate Clinical Research, Albany, NY; 6Multiple Sclerosis Center,
`The Chaim Sheba Medical Center, Tel Hashomer, Israel; 7Barrow
`Neurology Clinics at St. Joseph’s Hospital and Medical Center, Phoe-
`nix, AZ; 8George Washington University Medical Center, Department
`of Neurology, Washington, DC; 9Advanced Neurology Specialists,
`Great Falls, MT; 10INC Research, Inc., Raleigh, NC; 11Avanir Phar-
`maceuticals, San Diego, CA; 12Division of Neuroimmunology and MS
`Center, Carmel Medical Center, Haifa, Israel.
`
`Appendix of investigators on p. 787.
`
`Received May 25, 2005, and in revised form Jan 3, 2006. Accepted
`for publication Feb 6, 2006.
`
`InterScience
`in Wiley
`2006
`24,
`online Apr
`Published
`(www.interscience.wiley.com). DOI: 10.1002/ana.20828
`
`Address correspondence to Dr Panitch, University of Vermont Col-
`lege of Medicine, FAHC-UHC Campus, 1 South Prospect Street,
`Burlington, VT 05401. E-mail: hillel.panitch@vtmednet.org
`
`780 © 2006 American Neurological Association
`Published by Wiley-Liss, Inc., through Wiley Subscription Services
`
`Page 1 of 8
`
`Biogen Exhibit 2027
`Coalition v. Biogen
`IPR2015-01993
`
`

`

`neuroprotective in ALS patients suggested that DM/Q
`had a beneficial effect on PBA. This observation was
`then extended in a crossover study of PBA in ALS.14 In
`a recent phase III study in ALS patients with PBA, the
`combination of 30mg DM with 30mg Q given twice
`daily for 29 days significantly reduced the severity of
`PBA; reduced the incidence of crying or laughing epi-
`sodes, or both; and improved quality of life compared
`with DM or Q alone.15 This report describes a 3-month
`study to assess the safety and efficacy of DM/Q com-
`pared with placebo in MS patients with PBA.
`
`Patients and Methods
`Patients
`Patients were enrolled and treated between December 2002
`and June 2004 at 18 centers in the United States and 4
`centers in Israel
`in this multicenter, randomized, double-
`blinded, placebo-controlled study. Patients were required to
`have MS according to the International Panel (McDonald)
`criteria,16 a clinical diagnosis of PBA, and a score of 13 or
`more on the Center for Neurologic Study-Lability Scale
`(CNS-LS) at the day 1 clinic visit. The CNS-LS is a seven-
`item self-report questionnaire that provides a score for PBA
`ranging from 7 to 35. The CNS-LS has been validated in
`ALS17 and is the only instrument validated for the measure-
`ment of PBA in MS.18
`Patients were also required to have a normal electrocardio-
`gram (ECG); normal hematological, hepatic, and renal func-
`tion tests; no current or prior history of major psychiatric
`disturbance; and no coexistent systemic diseases that would
`interfere with interpretation of the results of the study. Pa-
`tients with any of the following ECG abnormalities were ex-
`cluded: heart block (any degree); prolongation of QTc inter-
`val (ⱖ450 milliseconds for male patients; ⱖ470 milliseconds
`for female patients); sinus bradycardia (⬍50 beats/min) or
`history of sick sinus syndrome; ventricular tachycardia, mul-
`tifocal ventricular ectopic beats (any frequency), or frequent
`unifocal ventricular ectopic beats (⬎5 per minute). Female
`patients had to practice an acceptable method of birth con-
`trol for at least 1 month before entry and during the study,
`or be surgically sterile or postmenopausal.
`Patients were not to take antidepressants, monoamine ox-
`idase inhibitors, anticoagulants, certain other inhibitors or
`substrates for P450 2D6 or P450 3A4, and over-the-counter
`or prescription medications containing DM or Q during the
`study. Treatment with concomitant disease-modifying drug
`for MS (eg, interferon-␤ or glatiramer acetate) must have
`been established at least 1 month before enrollment and had
`to be maintained at a constant dose throughout the study.
`Patients who experienced MS exacerbations were withdrawn
`from this study, because exacerbations themselves or treat-
`ment with corticosteroids could confound the efficacy assess-
`ments. The procedures for the final study visit were con-
`ducted at the time of withdrawal.
`
`Randomization and Blinding
`Patients were randomized in a 1:1 ratio to receive capsules
`containing either DM/Q (30mg/30mg) or placebo. Study
`medications were formulated in identical capsules that were
`
`distributed in identical packaging and were dispensed in
`strict sequence. Randomization was done in blocks to ensure
`approximately equal representation within treatment centers
`(Quintiles, Mt Laurel, NJ), and study drug was shipped di-
`rectly to the clinical sites. The sponsor, investigators, and
`patients were all blinded to treatment allocation.
`
`Treatment and Evaluations
`The study protocol and consent forms were approved by the
`institutional review boards of the participating institutions.
`Informed consent was obtained following the principles out-
`lined in the Declaration of Helsinki.
`Patients were instructed to take their study medication ev-
`ery 12 hours for 85 days and were given a diary to record the
`times when study medication was taken, the number of cry-
`ing and/or laughing episodes experienced daily, and adverse
`events (AEs). Patients were seen for safety and efficacy assess-
`ments on days 1, 15, 29, 57, and 85. The CNS-LS ques-
`tionnaire was administered at all clinic visits. The CNS-LS18
`includes questions regarding laughter and crying episodes
`and requires about 5 minutes to complete. Quality of life
`and quality of relationships were assessed at the same clinic
`visits using visual analog scales19 consisting of 10cm lines
`anchored with “not at all” on the left and “continuously” on
`the right. A pain intensity rating scale also was administered
`at all clinic visits. Patients were asked to indicate the amount
`of pain experienced within the previous 24 hours using a
`five-point scale in which none ⫽ 0; mild ⫽ 1; moderate ⫽
`2, severe ⫽ 3; and extreme ⫽ 4.
`Patients were questioned regarding AEs and vital signs were
`recorded at all clinic visits. ECGs and blood samples for lab-
`oratory testing were obtained at screening, day 29, and day 85;
`physical examination was performed at screening and day 85.
`Cytochrome P450 2D6 genotyping to identify each pa-
`tient’s ability to metabolize DM was performed on isolated
`genomic DNA by polymerase chain reaction analysis (Genais-
`sance Pharmaceuticals, Morrisville, NC). Based on the results,
`subjects were classified according to predicted phenotype as
`poor, intermediate, extensive, or ultrarapid metabolizers. These
`results were used for data evaluation only; patients were eligi-
`ble to enter the study regardless of genotype.
`Blood samples also were taken on days 29 and 85 (or the
`final visit) for the determination of concentrations of DM, the
`DM metabolite DX, and Q in plasma. Heparinized plasma
`samples were assayed (MDS Pharma Services, Lincoln, NE)
`using a validated high-performance liquid chromatography
`procedure for Q (limit of quantitation ⫽ 50ng/ml) and a val-
`idated liquid chromatography mass spectrometry/mass spec-
`trometry procedure for DM (limit of quantitation ⫽ 0.200ng/
`ml) and DX (limit of quantitation ⫽ 2.5ng/ml).
`The protocol-defined primary efficacy end point was
`change from baseline in the CNS-LS score. Secondary efficacy
`variables were the number of episodes of inappropriate crying
`and/or laughing per week, changes from baseline in visual an-
`alog scale scores for overall quality of life and quality of rela-
`tionships, and change from baseline in the pain intensity rat-
`ing scale score. Additional efficacy variables, not specified in
`the protocol, used to evaluate the data were the proportion of
`patients with complete remission (no episodes of PBA), pro-
`portion of patients who responded to treatment (at least a
`
`Panitch et al: Trial of DM/Q for PBA in MS
`
`781
`
`Page 2 of 8
`
`

`

`three-point decrease in CNS-LS), clinical effect by treatment
`period (proportion of patients with more than one episode per
`week), and the mean improvement in CNS-LS score by visit.
`
`Statistical Methods
`For analysis of continuous efficacy variables, mean change in
`each group’s score was assessed using the analysis of covari-
`ance method of Frison and Pocock20 with baseline CNS-LS
`measurement and indicator variables for center effect as co-
`variates. Episode counts were analyzed separately using a
`negative binomial regression model with center effects.21 Ef-
`ficacy comparisons were tested with a two-sided, 5% signif-
`icance level using SAS, Version 8.2 (SAS Institute, Cary,
`NC) or Stata, Version 8.2 (StataCorp, College Station, TX)
`to perform the analyses. Data analysis conformed to a
`protocol-defined statistical analysis plan.
`Change scores were measured as the difference between
`baseline scores (day 1) and the average of the four scores on
`days 15, 29, 57, and 85. If any scores were missing, the non-
`missing scores were averaged. All patients who took study
`medication were included in the intention to treat analysis.
`AEs were recorded and included in the safety analysis re-
`gardless of their relationship to treatment. The original terms
`used by the investigators to identify AEs in the case report
`form were translated into dictionary-coded preferred terms
`by using the Medical Dictionary for Regulatory Activities
`(MedDRA, Version 3.3 Maintenance and Support Services
`(MSSO), Reston, VA). Fisher’s exact test or likelihood ratio
`␹2 tests, as appropriate, were used to compare the AE rates
`(preferred terms) between treatment groups for all AEs oc-
`curring in 5% or more of patients in a treatment group.
`A sample size calculation determined that 48 patients in
`each randomized treatment group would be sufficient to de-
`tect a difference of 3 points in the CNS-LS score with 90%
`power. These calculations were based on an observed differ-
`ence of 3.4 units in the adjusted average improvement in
`CNS-LS scores with a residual standard deviation of 4.5 in
`the phase III randomized study of DM/Q in ALS patients.15
`
`Results
`Disposition and Demography
`The disposition of patients is illustrated in Figure 1. A
`total of 150 patients were randomized to treatment, 76
`in the DM/Q group and 74 in the placebo group. The
`proportion of patients who discontinued treatment was
`27.6% in the DM/Q group and 28.4% in the placebo
`group, with 11 patients (14.5%) in the DM/Q group
`and 8 patients (10.8%) in the placebo group discon-
`tinuing due to AEs (excluding MS exacerbations). The
`characteristics of the intention to treat population are
`given in Table 1. The treatment groups were compa-
`rable in baseline characteristics (all p ⱖ 0.103). Most
`patients in this study were extensive metabolizers of
`DM, and the treatment groups had similar frequencies
`of metabolizer phenotypes (Table 2).
`
`782 Annals of Neurology Vol 59 No 5 May 2006
`
`Efficacy
`PRIMARY EFFICACY MEASURE (CENTER FOR NEUROLOGIC
`Efficacy results are summa-
`STUDY-LABILITY SCALE).
`rized in Table 3. Patients who received DM/Q had a
`greater decrease in CNS-LS score during study com-
`pared with patients who received placebo (p ⬍ 0.0001);
`on average,
`the improvement
`for patients
`receiving
`DM/Q was more than twice that of placebo patients.
`The adjusted mean improvements in CNS-LS score
`were also compared for each visit separately. The esti-
`mated treatment effect by study day is shown in Figure
`2. Patients receiving DM/Q had a greater decrease in
`CNS-LS score than patients receiving placebo at each
`assessment (all p ⬍ 0.0001, t test for the linear regres-
`sion coefficient), and more patients receiving DM/Q
`responded to treatment with a three-point or greater
`decrease in mean CNS-LS than did patients receiving
`placebo ( p ⬍ 0.0001; see Table 3).
`
`SECONDARY EFFICACY MEASURES (EPISODE COUNTS, VI-
`SUAL ANALOG SCALE, AND PAIN INTENSITY RATING
`Patients treated with DM/Q experienced about
`SCALE).
`half as many episodes of inappropriate crying, laughing,
`or crying and laughing combined (all p ⱕ 0.0077; see
`Table 3); had greater improvement in overall quality of
`life and quality of relationships (p ⱕ 0.0001); and had a
`twofold greater decrease in pain intensity (p ⫽ 0.0271)
`compared with patients treated with placebo.
`Based on episode rates (see Table 3), DM/Q was sta-
`tistically superior to placebo as early as the first week of
`treatment. Fewer DM/Q patients had more than one
`episode per week during every time period after begin-
`ning treatment, and in the final period analyzed (weeks
`9–12), more than 65% of placebo patients had more
`than one episode per week, whereas only one-fourth of
`DM/Q patients did (p ⬍ 0.001). The proportion of pa-
`tients with complete remission, that is, no episodes of
`inappropriate crying and/or laughing, was also signifi-
`cantly greater in the DM/Q group during every 2-week
`study period and over the entire duration of the study.
`
`To provide clinical interpreta-
`ADDITIONAL ANALYSES.
`tion of the CNS-LS score in patients with MS, we com-
`pared changes in CNS-LS scores with the rate of episodes.
`In a study of DM/Q in patients with ALS,15 each increase
`of one point in the CNS-LS score corresponded to ap-
`proximately a 12% higher episode rate. When the same
`model was applied to this study’s results, each point on
`the CNS-LS corresponded to an increase of 11% in the
`episode rate, and a mean 7.7-point decrease in CNS-LS
`score in patients treated with DM/Q corresponded to an
`approximately 46% decrease in episode rate.
`To assess whether the severity of PBA at baseline in-
`fluenced the quantity or the timing of response, we clas-
`sified patients as having either moderate or severe PBA
`
`Page 3 of 8
`
`

`

`Fig 1. Disposition of patients. AVP-923 was the study code number for DM/Q (capsules containing dextromethorphan [DM] and
`quinidine [Q]).
`
`at baseline by splitting the sample at the median baseline
`CNS-LS score. The effect of DM/Q on episode rate was
`tested by using the negative binomial regression model
`in each severity category over several time periods. There
`was no discernible interaction of baseline severity with
`response to treatment (all p ⱖ 0.326).
`Sensitivity analyses for dropouts and missing data
`were performed. The number of patients with one or
`more missing observations was 29% overall and was
`approximately equal
`in the two treatment groups
`(21/76 for DM/Q and 22/74 for placebo). Two anal-
`
`issue using
`yses were performed to examine this
`Mallinckrodt and colleagues’22 strategy for examining
`dropouts. A last observation carried forward analysis
`produced an adjusted mean difference between DM/Q
`and placebo of 3.8 points (standard error ⫽ 0.8; p ⬍
`0.0001). A repeated-measures generalized estimating
`equations model with exchangeable correlation struc-
`ture, adjusting for center effects and common time
`trend, estimated a mean treatment difference of 4.6
`points (standard error ⫽ 0.7; p ⬍ 0.0001). Both of
`these sensitivity analyses agreed with the primary effi-
`
`Panitch et al: Trial of DM/Q for PBA in MS
`
`783
`
`Page 4 of 8
`
`

`

`Table 1. Demographics, Multiple Sclerosis and Pseudobulbar Affect History, and Baseline Values
`
`Characteristics
`
`DM/Q (n ⫽ 76)
`
`Placebo (n ⫽ 74)
`
`Mean age, yr (SD)
`Female sex, n (%)
`Race, n (%)
`White
`Black
`Asian
`Hispanic
`Other
`Mean years with MS (SD)
`Mean weekly episodes of crying and laughing (pa-
`tient estimate) (SD)
`Mean baseline (day 1) CNS-LS (SD)
`Mean baseline VAS, overall quality of life (SD)
`Mean baseline VAS, overall quality of relationships
`Mean baseline pain intensity rating scale
`
`46.3 (9.8)
`62 (81.6)
`
`68 (89.5)
`5 (6.6)
`1 (1.3)
`2 (2.6)
`0 (0.0)
`10.3 (8.6)
`14.1 (20.4)
`
`20.3 (5.0)
`50.4 (28.4)
`45.6 (28.8)
`1.4 (1.0)
`
`43.7 (10.0)
`62 (83.8)
`
`68 (91.9)
`5 (6.8)
`0 (0.0)
`1 (1.4)
`0 (0.0)
`9.6 (7.4)
`17.3 (25.2)
`
`21.4 (5.1)
`54.1 (27.5)
`49.2 (27.5)
`1.4 (1.0)
`
`pa
`
`0.1033
`0.7214
`0.7275
`
`0.5751
`0.4048
`
`0.1683
`0.4206
`0.4233
`0.8206
`
`ap values to compare means for continuous variables were computed by using t tests. p values for categorical variables were computed by using ␹2 tests.
`DM/Q ⫽ capsules containing dextromethorphan and quinidine; SD ⫽ standard deviation; MS ⫽ multiple sclerosis; CNS-LS ⫽ Center for
`Neurologic Study–Lability Scale; VAS ⫽ visual analog scale.
`
`cacy analysis and indicated that dropouts did not dif-
`ferentially bias the assessment of efficacy in this study.
`
`Safety
`The proportions of patients who
`ADVERSE EVENTS.
`had any AEs, had serious adverse events (SAEs), or had
`AEs that resulted in discontinuation were similar be-
`tween treatment groups. Eleven (14.5%) patients in
`the DM/Q group and eight patients (10.8%) in the
`placebo group discontinued the study or stopped med-
`ication due to AEs. Four patients in the DM/Q group
`and six patients in the placebo group were dropped
`from the study because of MS exacerbations. At least 1
`AE was reported by 62 (81.6%) DM/Q patients and
`63 (85.1%) placebo patients. Six patients had SAEs,
`two (2.6%) in the DM/Q group and four (5.4%) in
`the placebo group; none of the SAEs was judged by the
`investigators to be related to study treatment. AEs ex-
`perienced by at least 5% of patients within a treatment
`group are summarized in Table 4.
`Headache was the most common AE, but it occurred
`in more placebo patients than DM/Q patients, although
`the difference was not significant. Nausea was reported
`for more DM/Q patients than placebo patients, but this
`
`difference also was not significant. The median duration
`of nausea was 1.5 days in DM/Q patients and 1.0 day
`in placebo patients. Dizziness was the only AE that oc-
`curred significantly more frequently in DM/Q patients
`than in placebo patients; but most instances of dizziness
`were mild or moderate, and only one patient, in the
`DM/Q group, reported severe dizziness. The number of
`patients reporting fatigue was 15 in both groups, al-
`though the median duration of fatigue was 1.5 days in
`DM/Q patients and 3.0 days in placebo patients.
`
`OTHER SAFETY RESULTS. There was no significant dif-
`ference between treatment groups for shifts in any labora-
`tory value, and there was no significant shift within a
`treatment group for any laboratory value. There were no
`clinically relevant changes from baseline in vital signs or
`physical examination results for either treatment group.
`No significant difference between treatment groups was
`noted for the ECG parameters: HR, PR, QT, or QRS.
`The DM/Q group had a significantly greater change from
`screening to day 85 than the placebo group in QTc, but
`the QTc change was small (mean increase of 7.5 millisec-
`onds in the DM/Q group vs 0.3 millisecond in the pla-
`cebo group; p ⫽ 0.0236). No patient in either treatment
`
`Table 2. Number (%) of Patients with Predicted Phenotype for Metabolism of Dextromethorphan
`
`Predicted Phenotype
`
`DM/Q (n ⫽ 76)
`
`Placebo (n ⫽ 74)
`
`Total with phenotype data, n
`Poor
`Intermediate
`Extensive
`Ultrarapid
`
`50
`1 (2.0%)
`0 (0.0%)
`48 (96.0%)
`1 (2.0%)
`
`DM/Q ⫽ capsules containing dextromethorphan and quinidine.
`
`784 Annals of Neurology Vol 59 No 5 May 2006
`
`53
`2 (3.8%)
`1 (1.9%)
`50 (94.3%)
`0 (0.0%)
`
`Total
`(n ⫽ 150)
`
`103
`3 (2.9%)
`1 (1.0%)
`98 (95.1%)
`1 (1.0%)
`
`Page 5 of 8
`
`

`

`Table 3. Summary of Efficacy Results
`
`Efficacy Variable
`
`Primary efficacy variable
`Adjusted mean change in CNS-LS score (SE)a–c
`Secondary efficacy variables
`Adjusted mean change in overall quality of life VAS
`score (SE)b,c
`Adjusted mean change in quality of relationships
`VAS score (SE)b,c
`Adjusted mean change in pain intensity rating scale
`score (SE)b,c
`Mean number of episodes per week (SD)d
`Inappropriate crying
`Inappropriate laughing
`Inappropriate crying and laughing
`Additional efficacy variables
`Proportion of patients with complete remission (no
`episodes of inappropriate crying and/or laughing),
`%e
`Week 1
`Weeks 2–3
`Weeks 4–5
`Weeks 6–8
`Weeks 9–12
`Weeks 1–12
`Proportion of responders (at least a three-point de-
`crease in mean CNS-LS during treatment), %e
`Clinical effect by treatment period: proportion of
`patients with more than one episode per week, %e
`Week 1
`Weeks 2–3
`Weeks 4–5
`Weeks 6–8
`Weeks 9–12
`
`DM/Q (n ⫽ 76)
`
`Placebo (n ⫽ 74)
`
`p
`
`7.7 (0.6)
`
`32.1 (2.7)
`
`31.0 (2.9)
`
`0.4 (0.1)
`
`2.2 (4.9)
`2.5 (8.4)
`4.7 (10.9)
`
`21.9
`28.6
`46.2
`45.9
`45.6
`20.8
`83.6
`
`64.3
`45.2
`32.8
`39.7
`25.9
`
`3.3 (0.6)
`
`14.9 (2.7)
`
`16.1 (2.8)
`
`0.2 (0.1)
`
`6.7 (10.8)
`4.8 (13.4)
`11.5 (19.4)
`
`8.3
`13.9
`12.3
`13.1
`21.1
`6.9
`49.3
`
`81.4
`82.3
`77.6
`70.0
`65.4
`
`⬍0.0001
`
`⬍0.0001
`
`0.0001
`
`0.0271
`
`⬍0.0001
`0.0077
`0.0002
`
`0.036
`0.040
`⬍0.001
`⬍0.001
`0.009
`0.028
`⬍0.0001
`
`0.046
`⬍0.001
`⬍0.001
`⬍0.001
`⬍0.001
`
`aChange in Center for Neurologic Study-Lability Scale (CNS-LS) was defined as baseline CNS-LS minus the mean of the scores on days 15,
`29, 57, and 85.
`bp value from linear regression, Frison and Pocock analysis of covariance, with adjustment for baseline value and center.
`cLeast squares means were computed from a regression model for individual with CNS-LS of 20 at baseline and average of center effects.
`dp value from negative binomial regression.
`ep value from Fisher’s exact test.
`DM/Q ⫽ capsules containing dextromethorphan and quinidine; SE ⫽ standard error; VAS ⫽ visual analog scale; SD ⫽ standard deviation.
`
`group had an increase in QTc greater than 59 millisec-
`onds from screening to either follow-up visit, or a QTc
`greater than 500 milliseconds at either follow-up visit.
`
`CORRELATION OF DRUG CONCENTRATIONS IN PLASMA
`WITH CENTER FOR NEUROLOGIC STUDY-LABILITY SCALE
`RESPONSE. Concentration data for patients of all phe-
`notypes who had plasma samples taken within 12 hours
`after dosing are shown in Table 5. Mean levels of DM,
`DX, and Q did not differ between days 29 and 85. Cor-
`relation analysis between concentration of DM in plasma
`and CNS-LS score, using patients from both treatment
`groups who had plasma samples taken within 12 hours of
`dosing, showed a significant negative correlation on both
`day 29 (n ⫽ 119; correlation coefficient ⫽ ⫺0.5041; p ⬍
`0.0001) and day 85 (n ⫽ 90; correlation coefficient ⫽
`
`⫺0.4169; p ⬍ 0.0001), indicating that CNS-LS scores
`decreased with increasing plasma DM levels.
`
`Discussion
`The robust efficacy results in this study of MS patients
`parallel those of a previous study in ALS patients.15
`Furthermore, the extended treatment period (85 vs 29
`days in the ALS study) supports the durability of effect
`in the management of PBA with DM/Q. The MS trial
`also differed from the ALS study in that DM/Q was
`compared with a placebo, whereas in the ALS trial, the
`effect of DM/Q was compared with each of its com-
`ponents. The individual components were ineffective,
`obviating further need for such testing. The primary
`end point of this study, reduction in CNS-LS score,
`was highly significant in favor of DM/Q. The results
`
`Panitch et al: Trial of DM/Q for PBA in MS
`
`785
`
`Page 6 of 8
`
`

`

`patients must report pain, and concurrent pain medi-
`cations were allowed during the study. Nevertheless,
`the reduction seen in the DM/Q treatment group was
`significantly different
`from placebo-treated patients,
`and reported pain decreased approximately 29% from
`baseline. Reported concomitant medications included
`fentanyl, gabapentin, lidocaine, oxycodone, tramadol,
`and hydrocodone, as well as over-the-counter analge-
`sics. Considering these aspects of the study design, the
`effects on pain appeared to be robust. The combina-
`tion of Q with DM resulted in sustained, therapeutic
`levels of DM in plasma over a 12-week treatment pe-
`riod; and higher DM levels correlated with decreased
`symptoms of PBA, as determined with the CNS-LS.
`The safety profile of DM/Q was favorable. Of the AEs
`reported in 5% or more of the patients, a statistically sig-
`nificant difference between DM/Q and placebo patients
`was observed only for dizziness. The discontinuation rate
`due to AEs in this study was notably less than that re-
`ported in the similar study of DM/Q in ALS patients
`(24% in the DM/Q group). In the ALS study,15 many of
`the discontinuations were due to musculoskeletal com-
`plaints that did not occur in the MS patients. No results
`of concern were observed in ECG or laboratory assess-
`ments.
`The mechanism of action of DM/Q in regulating
`PBA remains uncertain. DM has many pharmacological
`properties that may be involved: it is a weak uncompeti-
`tive N-methyl-D-aspartate8,9 receptor antagonist, a ␴-1
`receptor agonist,7 and there is also evidence that it can
`modulate serotonin release (5-hydroxytryptamine recep-
`tors).23 Interestingly, neurons in the brainstem and cer-
`
`Fig 2. Improvement in Center for Neurologic Study-Lability
`Scale (CNS-LS) score from baseline by study day. Values shown
`are least squares means, adjusting for baseline levels and center
`effects. AVP-923 was the study code number for DM/Q (cap-
`sules containing dextromethorphan [DM] and quinidine [Q]).
`
`of sensitivity analyses indicated that dropouts did not
`bias the assessment of efficacy in this study. The sec-
`ondary end points were all also significant in favor of
`DM/Q. The onset of efficacy of DM/Q was rapid, as
`early as the first week of treatment, and complete re-
`mission (no episodes at all) was achieved in a signifi-
`cant proportion of actively treated patients.
`MS patients often report disabling pain. Decreased
`glutamatergic signaling may alleviate pain, and thus it
`was hypothesized that DM/Q may be helpful in this
`aspect of MS. The study was not powered to observe
`an effect on pain, there was no entry requirement that
`
`Table 4. Adverse Events Reported by 5% or More of Patients
`
`Preferred Term
`
`DM/Q (n ⫽ 76)
`
`Placebo (n ⫽ 74)
`
`Abdominal pain NOS, n (%)
`Arthralgia, n (%)
`Back pain, n (%)
`Dermatitis NOS, n (%)
`Diarrhea NOS, n (%)
`Dizziness (except vertigo), n (%)
`Ecchymosis, n (%)
`Fatigue, n (%)
`Fatigue aggravated, n (%)
`Headache NOS, n (%)
`Insomnia NEC, n (%)
`Nasopharyngitis, n (%)
`Nausea, n (%)
`Pain NOS, n (%)
`Pain in limb, n (%)
`Pyrexia, n (%)
`Upper respiratory tract infection NOS, n (%)
`Vomiting NOS, n (%)
`Weakness, n (%)
`
`5 (6.6)
`6 (7.9)
`4 (5.3)
`2 (2.6)
`6 (7.9)
`20 (26.3)
`3 (3.9)
`11 (14.5)
`4 (5.3)
`12 (15.8)
`4 (5.3)
`3 (3.9)
`17 (22.4)
`6 (7.9)
`4 (5.3)
`3 (3.9)
`5 (6.6)
`3 (3.9)
`8 (10.5)
`
`3 (4.1)
`9 (12.2)
`4 (5.4)
`6 (8.1)
`6 (8.1)
`7 (9.5)
`5 (6.8)
`6 (8.1)
`9 (12.2)
`22 (29.7)
`4 (5.4)
`6 (8.1)
`11 (14.9)
`6 (8.1)
`8 (10.8)
`5 (6.8)
`6 (8.1)
`6 (8.1)
`4 (5.4)
`
`pa
`
`0.7192
`0.4256
`1.0000
`0.1637
`1.0000
`0.0100
`0.4914
`0.3038
`0.1561
`0.0515
`1.0000
`0.3237
`0.2962
`1.0000
`0.2422
`0.4914
`0.7634
`0.3237
`0.3680
`
`aFisher’s exact test to compare proportion of events across treatment groups.
`DM/Q ⫽ capsules containing dextromethorphan and quinidine; NOS ⫽ not otherwise specified; NEC ⫽ not elsewhere classified.
`
`786 Annals of Neurology Vol 59 No 5 May 2006
`
`Page 7 of 8
`
`

`

`Table 5. Concentration in Plasma for All Phenotypes
`Combined
`
`DM/Q (n ⫽ 76)
`
`Placebo (n ⫽
`74)
`
`Visit
`
`DM DX
`
`Q DM DX Q
`
`Day 29
`60
`n
`114.6
`Mean, ng/ml
`56.5
`SD
`Median, ng/ml 108.4
`Day 85
`43
`n
`114.7
`Mean, ng/ml
`48.06
`SD
`Median, ng/ml 114.8
`
`60
`82.2
`31.5
`77.1
`
`43
`78.6
`33.7
`75.9
`
`60
`162.1
`95.8
`144.0
`
`43
`168.4
`103.8
`167.6
`
`59
`0.0
`0.0
`0.0
`
`47
`0.1
`0.5
`0.0
`
`59
`0.9
`6.9
`0.0
`
`47
`0.5
`3.6
`0.0
`
`59
`0.0
`0.0
`0.0
`
`47
`0.0
`0.0
`0.0
`
`Two placebo patients had measurable concentrations of dextrometho-
`rphan (DM) and/or dextrorphan (DX). One patient, whose pheno-
`type was not determined, had a DX concentration of 53.3ng/ml at
`the day 29 visit; his concomitant medication record indicated that he
`took Theraflu, which contains DM, around this time. The other pa-
`tient, an extensive metabolizer, had a DM concentration of 3.6ng/ml
`and a DX concentration of 24.6ng/ml at the day 85 visit; however,
`her concomitant medication record identified no medications con-
`taining DM around the time of this plasma sample.
`Q ⫽ quinidine; SD ⫽ standard deviation.
`ebellum are richly decorated with ␴-1 receptors, suggest-
`ing that the effect of DM on emotional control may be
`mediated at least partially through ␴-1 receptor interac-
`tions. As a ␴-1 receptor agonist, DM would inhibit re-
`lease of glutamate, and as an uncompetitive N-methyl-
`D-aspartate receptor antagonist, it would suppress the
`response to excitatory neurotransmitters.
`The combination of 30mg Q with 30mg DM was
`effective and well tolerated in treating PBA in patients
`with MS. Because the pathophysiology of PBA is con-
`sidered to be similar regardless of the underlying dis-
`order, it is likely that DM/Q could provide an effective
`therapy for PBA associated with other neurological dis-
`eases or injuries in addition to the ALS and MS patient
`populations in which it has been studied.
`
`This study was supported by Avanir Pharmaceuticals (02-AVR-106,
`H.S.P., D.R.W., J.P.W., A.A., T.L.V., R.N.M., D.W.D., A.M.).
`
`Appendix
`The following investigators participated in Study 02-AVR-
`106: United States: J. D. Burkholder, D. W. Dietrich, H. D.
`Ehrenfeld, B. Steingo, J. Herbert, D. A. Konanc, R. N.
`Mandler, H. S. Panitch, A. D. Rae-Grant, C. Mihai, C. H.
`Smith, J. D. Sweeney, T. L. Vollmer, J. P. Wymer, D. R.
`Wynn, M. J. Patel, J. R. Huddlestone, G. L. Pattee; Israel:
`A. Achiron, A. Karni, S. S. Flechter, A. Miller.
`
`References
`1. Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and
`neurobehavioral correlates of pathological laughing and crying
`in multiple sclerosis. Arch Neurol 1997;54:1116