PRIME: Safety and Efficacy of AVP-923 in the Treatment of Central Neuropathic Pain in Multiple Sclerosis

• Sponsor: Avanir Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01324232
• Collaborator: (none)
• Enrollment: 209
• Locations: 72
• Arms: 4
• Actual Duration (Months): 24.6
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Central Neuropathic Pain; Multiple Sclerosis	Drug: AVP-923-45; Drug: AVP-923-30; Drug: AVP-923-20; Drug: Placebo	Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 209 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-blind, Randomized, Placebo-controlled, Four-arm, Multicenter, Dose-finding Study to Assess the Safety and Efficacy of Three Dose Levels of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Central Neuropathic Pain in Patients With Multiple Sclerosis
• Actual Study Start Date: Sep 8, 2011
• Actual Primary Completion Date: Sep 26, 2013
• Actual Study Completion Date: Sep 26, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo	Drug: Placebo; Matching placebo capsules administered once daily for first 7 days followed by twice daily for 11 weeks of the study to complete 12 weeks of treatment.
Experimental: AVP-923-45	Drug: AVP-923-45; AVP-923-45 (dextromethorphan 45 mg/quinidine 10 mg) capsules administered once daily for first 7 days followed by twice daily for 11 weeks of the study to complete 12 weeks of treatment.
Experimental: AVP-923-30	Drug: AVP-923-30; AVP-923-30 (dextromethorphan 30 mg/quinidine 10 mg) capsules administered once daily for first 7 days followed by twice daily for 11 weeks of the study to complete 12 weeks of treatment.
Experimental: AVP-923-20	Drug: AVP-923-20; AVP-923-20 (dextromethorphan 20 mg/quinidine 10 mg) capsules administered once daily for first 7 days followed by twice daily for 11 weeks of the study to complete 12 weeks of treatment.; Other Names: Nuedexta

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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.

2. 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,

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

Other Outcome Measures

1. Change From Baseline in Modified Ashworth Scale (MAS) Scores [Baseline; Day 85]

   MAS is not considered as a true endpoint. MAS scores were assessed at Baseline only. Change from Baseline could not be calculated because data for the later timepoints was not collected.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Main Inclusion Criteria:

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 Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	North Central Neurology Associates PC	Cullman	Alabama	United States	35058
2	St. Joseph's Hospital Medical Center	Phoenix	Arizona	United States	85013
3	Alta Bates Summit Medical Center	Berkeley	California	United States	94705
4	University of California, Irvine	Orange	California	United States	92868
5	Coordinated Clinical Research	San Diego	California	United States	92103
6	University of California, San Francisco	San Francisco	California	United States	94158
7	University of Colorado	Aurora	Colorado	United States	80045
8	Neurology Associates, PA	Maitland	Florida	United States	32751
9	Collier Neurologic Specialists	Naples	Florida	United States	34102
10	Laszlo J. Mate, MD	North Palm Beach	Florida	United States	33408
11	Neurology Associates of Ormond Beach	Ormond Beach	Florida	United States	32174
12	Neurological Associates	Pompano Beach	Florida	United States	33060
13	Neurologique Foundation	Ponte Vedra Beach	Florida	United States	32082-4040
14	Suncoast Neuroscience Associates, Inc.	Saint Petersburg	Florida	United States	33713
15	University of South Florida	Tampa	Florida	United States	33612
16	Geodyssey Research, LLC	Vero Beach	Florida	United States	32960
17	Shepard Center	Atlanta	Georgia	United States	30309
18	Rush-Presbyterian St. Luke's Medical Center	Chicago	Illinois	United States	60612
19	Consultants in Neurology	Northbrook	Illinois	United States	60062
20	Josephson Wallack Munshower Neurology, P.C.	Indianapolis	Indiana	United States	46256
21	MidAmerica Neuroscience Institute	Lenexa	Kansas	United States	66214
22	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21287
23	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
24	Michigan Neurology Associates, P.C.	Clinton Township	Michigan	United States	48035
25	Wayne State University	Detroit	Michigan	United States	48201
26	Henry Ford Health System	Detroit	Michigan	United States	48202
27	Advanced Neurology Specialists	Great Falls	Montana	United States	59405
28	Neurology Associates PC	Lincoln	Nebraska	United States	68506
29	Albany Medical Center Hospital	Albany	New York	United States	12208
30	NYU-Hospital for Joint Diseases	New York	New York	United States	10003
31	University of Rochester	Rochester	New York	United States	14642
32	SUNY at Stony Brook	Stony Brook	New York	United States	11794
33	Carolinas Medical Center	Charlotte	North Carolina	United States	28207
34	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
35	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma	United States	73104
36	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19107
37	Geisinger Health System	Wilkes-Barre	Pennsylvania	United States	18711
38	Advanced Neurosciences Institute	Franklin	Tennessee	United States	37064
39	Baylor College of Medicine	Houston	Texas	United States	77030
40	Rocky Mountain MS Clinic	Salt Lake City	Utah	United States	84103
41	Neurological Associates	Henrico	Virginia	United States	23226
42	MS Center of Greater Washington	Vienna	Virginia	United States	22182
43	Swedish Medical Center	Seattle	Washington	United States	98122
44	MultiCare Health System	Tacoma	Washington	United States	98405
45	Instituto de Neurologia Cognitiva	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1126AAB
46	Hospital Britanico de Buenos Aires	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1280AEB
47	Hospital Italiano	Ciudad Autónoma de Buenos Aires	Buenos Aires	Argentina	C1181ACH
48	Instituto Argentino de Investigacion Neurologica	Ciudad de Buenos Aires	Buenos Aires	Argentina	C1015ABR
49	Hospital Churruca-Visca	Buenos Aires		Argentina	C1437JCH
50	Fundación Argentina Contra las Enfermedades Neurológicas del Envejecimiento - FACENE	Buenos Aires		Argentina	CP1117ABD
51	Medeos - Centro de Medicina Integral e Investigación Clínica	Ciudad Autonoma de Buenos Aires		Argentina
52	Instituto de Neurología y Neurorrehabilitación del Litoral	Santa Fe		Argentina
53	Fakultni nemocnice u sv. Anny v Brne	Brno		Czechia
54	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 0
55	Nemocnice Jihlava, prispevkova organizace	Jihlava		Czechia	586 33
56	Fakultni Nemocnice Ostrava	Ostrava		Czechia	708 52
57	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 21
58	Szpital Powiatowy w Czeladzi	Czeladz		Poland	41-250
59	Pomorskie Centrum Traumatologii im. M. Kopernika w Gdansku	Gdansk		Poland	80-803
60	Diagnomed Clinical Research Sp. z.o.o.	Katowice		Poland	40-594
61	Niepubliczny Zaklad Opieki Zdrowotnej NEURO-MEDIC	Katowice		Poland	40-752
62	Niepubliczny Zaklad Opieki Zdrowotnej PROFILAKTYKA	Katowice		Poland
63	Zespol Opieki Zdrowotnej w Konskich	Konskie		Poland	26-200
64	Specjalistyczny Gabinet Neurologiczny	Plewiska		Poland	62-064
65	Niepubliczny Zaklad Opieki Zdrowotnej NEURO-KARD Ilkowski i Partnerzy Spolka Partnerska Lekarzy	Poznan		Poland	61-289
66	Osrodek Badan Klinicznych Indywidualnej Specjalistycznej Praktyki Lekarskiej	Szczecin		Poland	70-215
67	Hospital del Mar	Barcelona	Cataluña	Spain	08003
68	Hospital Vall D´Hebron	Barcelona	Cataluña	Spain	08035
69	Hospital Universitari de Girona Dr. Josep Trueta	Girona	Cataluña	Spain	17007
70	Hospital Universitario Virgen de la Arrixaca	El Palmar	Murcia	Spain	30120
71	Hospital Univ. Nuestra Sra. De La Candelaria	Santa Cruz De Tenerife		Spain	38010
72	Hospital Universitario Vírgen Macarena	Sevilla		Spain	41009

Sponsors and Collaborators

• Avanir Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Avanir Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01324232
• Other Study ID Numbers: 11-AVR-130
• First Posted: Mar 28, 2011
• Last Update Posted: Nov 22, 2021
• Last Verified: Oct 1, 2021

• Additional relevant MeSH terms: Multiple Sclerosis; Neuralgia; Sclerosis; Quinidine; Dextromethorphan

Study Results

Participant Flow

Pre-assignment Detail	After screening procedures, participants underwent a 1-week washout period for all analgesic medications, with the exception of ibuprofen in doses that did not exceed 800 milligrams per day (mg/day).

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Period Title: Overall Study
STARTED	49	53	54	53
COMPLETED	44	42	41	42
NOT COMPLETED	5	11	13	11

Baseline Characteristics

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Total of all reporting groups
Overall Participants	49	53	54	53	209
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.7 (8.41)	47.2 (9.20)	49.1 (11.21)	48.1 (13.04)	48.5 (10.63)
Sex: Female, Male (Count of Participants)
Female	9 18.4%	7 13.2%	12 22.2%	12 22.6%	40 19.1%
Male	40 81.6%	46 86.8%	42 77.8%	41 77.4%	169 80.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	43 87.8%	46 86.8%	49 90.7%	48 90.6%	186 89%
Black or African American	3 6.1%	4 7.5%	5 9.3%	4 7.5%	16 7.7%
Asian	1 2%	0 0%	0 0%	0 0%	1 0.5%
Hispanic or Latino	2 4.1%	3 5.7%	0 0%	1 1.9%	6 2.9%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline; Days 57 through 84 (PRS score); Days 22 and 50 (dextromethorphan plasma concentrations)

Outcome Measure Data

Analysis Population Description

Modified Intention-To-Treat (MITT) Population: all participants in the ITT Population (randomized participants) who received at least one dose of study drug, provided a Baseline PRS score, and had at least one post-Baseline PRS assessment. Analysis was based on the randomized treatment assigned (regardless of actual treatment received).

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	All participants who received placebo, AVP-923-20, AVP-923-30, or AVP-923-45 treatments during the study.
Measure Participants	49	53	54	53	209
Median (Full Range) [units on a scale]	-1.821	-2.143	-2.650	-1.679	-2.000

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Total
	Comments	The null hypothesis that the true correlation between the change from Baseline PRS scores and the DM plasma concentration was equal to zero and was tested using a 2-sided test at the 5% level of significance within active treatment groups. The regression line was fitted using change from baseline in average PRS during Day 57-84 as the dependent variable and the average of log-transformed DM Plasma Concentration at Day 22 and Day 50 as the independent variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.9827
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Pearson correlation
	Estimated Value	0.0019
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Average Logarithms of Dextromethorphan (DM) Plasma Concentrations (Cmax) on Days 22 and 50
Description	The average of the logarithms of the DM plasma concentrations on Days 22 and 50 were presented.
Time Frame	0 to 3 hours post-dose on Day 22 and 50

Outcome Measure Data

Analysis Population Description

MITT Population. Only participants with available data were analyzed.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	All participants who received placebo, AVP-923-20, AVP-923-30, or AVP-923-45 treatments during the study.
Measure Participants	0	43	45	45	133
Median (Full Range) [Log Micrograms per Liter]	4.019	4.493	4.758	4.394

3. Secondary Outcome

Title	Comparison of the Adjusted Mean Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84
Description	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.
Time Frame	Baseline; Days 57 through 84

Outcome Measure Data

Analysis Population Description

MITT Population. Analysis was carried out using an analysis of covariance (ANCOVA) model, with the PRS score change from Baseline to Days 57-84 as the dependent variable, treatment group as a fixed effect, and the Baseline PRS score as a covariate.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	AVP-923-20 and AVP-923-30	AVP-923-30 and AVP-923-45	All AVP-923
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received either AVP-923-20 or AVP-923-30 in the morning during the first 7 days of the study. Participants then received one capsule of AVP-20 or AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received either AVP-923-30 or AVP-923-45 in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 or AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	All participants receiving AVP-923-20, AVP-923-30, or AVP-923-45.
Measure Participants	49	53	54	53	107	107	160
Least Squares Mean (Standard Error) [units on a scale]	-2.04 (0.332)	-2.07 (0.319)	-2.41 (0.316)	-2.00 (0.319)	-2.24 (0.224)	-2.21 (0.225)	-2.16 (0.184)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45, Total, AVP-923-30 and AVP-923-45, All AVP-923
	Comments	Test of dose trend (overall P value)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.8869
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments	Pairwise treatment group vs placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9381
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.94 to 0.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.46
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments	Pairwise treatment group vs placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.4128
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -1.28 to 0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.46
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments	Pairwise treatment group vs placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9427
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.88 to 0.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.461
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Total
	Comments	Pairwise treatment group vs placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.6075
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.401
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30 and AVP-923-45
	Comments	Pairwise treatment group vs placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.6690
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.96 to 0.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.402
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, All AVP-923
	Comments	Pairwise treatment group vs placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.7394
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.88 to 0.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.38
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline in Fatigue Severity Scale (FSS) Scores at Days 57 Through 84
Description	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,
Time Frame	Baseline; Days 57 through 84

Outcome Measure Data

Analysis Population Description

MITT Population. Only those participants with available data were analyzed.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Measure Participants	48	52	54	53
Least Squares Mean (Standard Error) [units on a scale]	-3.32 (1.742)	-2.00 (1.680)	-6.32 (1.642)	-2.12 (1.662)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9731
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; -3.46 to 6.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.42
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	-3
	Confidence Interval	(2-Sided) 95%; -7.72 to 1.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.394
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -3.54 to 5.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.408
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at Days 22 and 85
Description	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.
Time Frame	Baseline; Days 22 and 85

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least 1 dose of study drug. Only participants with a value at both the Baseline visit and the specific post-Baseline visit have been included in the analysis. Safety analyses were performed on the safety population based on the treatment participants actually received.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	All participants receiving placebo, AVP-923-20, AVP-923-30, or AVP-923-45.
Measure Participants	49	54	53	53	209
Day 22	-0.1 (0.35)	-0.1 (0.56)	-0.2 (0.67)	-0.0 (0.63)	-0.1 (0.56)
Day 85	-0.1 (0.75)	-0.1 (0.67)	-0.1 (0.46)	0.0 (0.58)	-0.1 (0.62)

6. Secondary Outcome

Title	Mean Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores at Day 85
Description	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.
Time Frame	Baseline; Day 85

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Measure Participants	49	53	54	53
Least Squares Mean (Standard Error) [units on a scale]	-4.84 (2.651)	-4.34 (2.551)	-6.50 (2.526)	-1.41 (2.550)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.4778
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; -6.76 to 7.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.676
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.67
	Confidence Interval	(2-Sided) 95%; -8.89 to 5.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.663
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	3.43
	Confidence Interval	(2-Sided) 95%; -3.83 to 10.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.681
	Estimation Comments

7. Secondary Outcome

Title	Mean Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores at Day 85
Description	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.
Time Frame	Baseline; Day 85

Outcome Measure Data

Analysis Population Description

MITT Population. For participants with missing data at Day 85, the last available value has been used.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Measure Participants	49	53	54	53
Least Squares Mean (Standard Error) [units on a scale]	-0.51 (0.490)	-1.02 (0.471)	-1.36 (0.467)	-1.71 (0.472)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0685
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -1.85 to 0.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.68
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	-0.85
	Confidence Interval	(2-Sided) 95%; -2.19 to 0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.677
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -2.54 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.681
	Estimation Comments

8. Secondary Outcome

Title	Mean Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores at Day 85
Description	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.
Time Frame	Baseline; Day 85

Outcome Measure Data

Analysis Population Description

MITT Population. Only those participants with available data were analyzed. For participants with missing data at Day 85, the last available value has been used.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Measure Participants	48	52	54	53
Least Squares Mean (Standard Error) [units on a scale]	-0.99 (1.058)	-1.48 (1.020)	-1.88 (0.998)	0.47 (1.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.4201
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -3.40 to 2.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.473
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.90
	Confidence Interval	(2-Sided) 95%; -3.76 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.454
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; -1.42 to 4.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.46
	Estimation Comments

9. Secondary Outcome

Title	Mean Change From Baseline in Beck Depression Inventory (BDI-II) Scores at Day 85
Description	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.
Time Frame	Baseline; Day 85

Outcome Measure Data

Analysis Population Description

MITT Population. For participants with missing data at Day 85, the last available value has been used.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Measure Participants	49	53	54	53
Least Squares Mean (Standard Error) [units on a scale]	0.83 (0.868)	-0.26 (0.835)	0.21 (0.828)	1.15 (0.837)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.8068
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.10
	Confidence Interval	(2-Sided) 95%; -3.47 to 1.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.205
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -2.99 to 1.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.2
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; -2.07 to 2.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.207
	Estimation Comments

10. Secondary Outcome

Title	Mean Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores at Day 85
Description	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.
Time Frame	Baseline; Day 85

Outcome Measure Data

Analysis Population Description

MITT Population. Only those participants with available data were analyzed. For participants with missing data at Day 85, the last available value has been used.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
Measure Participants	48	52	54	53
Total correct responses, Oral	0.59 (2.045)	2.96 (1.881)	1.91 (1.525)	2.06 (1.809)
Total correct responses, Written	1.85 (1.111)	3.62 (1.086)	0.16 (1.158)	0.20 (1.083)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.6315
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect. Oral responses.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	2.37
	Confidence Interval	(2-Sided) 95%; -3.19 to 7.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.772
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; -3.83 to 6.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.562
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; -4.01 to 6.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.728
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1485
	Comments	P-value presented tests the hypothesis for overall treatment effect versus no treatment effect. Written responses.
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; -1.31 to 4.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.558
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-30
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	-1.68
	Confidence Interval	(2-Sided) 95%; -4.86 to 1.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.605
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean difference (final values)
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -4.71 to 1.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.549
	Estimation Comments

11. Secondary Outcome

Title	Mean Numerical Rating Scale (NRS) Scores at Days 22, 50, and 85
Description	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.
Time Frame	Days 22, 50, and 85

Outcome Measure Data

Analysis Population Description

MITT Population. Only participants with a value at both the Baseline visit and the specific post-Baseline visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	All participants receiving placebo, AVP-923-20, AVP-923-30, or AVP-923-45.
Measure Participants	49	53	54	53	209
Day 22	3.29 (2.717)	3.56 (3.016)	3.41 (2.723)	3.90 (2.649)	3.54 (2.762)
Day 50	3.24 (2.721)	2.89 (2.633)	4.06 (2.888)	3.54 (2.364)	3.42 (2.666)
Day 85	3.66 (2.869)	3.13 (3.085)	3.87 (2.825)	3.36 (2.666)	3.50 (2.857)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments	The null hypothesis is that the true correlation between NRS scores and DM plasma concentration is equal to zero. Only 158 of the 209 participants in the mITT Population were analyzed at Day 22.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1404
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments	The null hypothesis that the true correlation between NRS scores and DM plasma concentration is equal to zero. Only 152 of the 209 participants in the mITT Population were analyzed at Day 50.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0805
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments	The null hypothesis that the true correlation between NRS scores and DM plasma concentration is equal to zero. Only 185 of the 209 participants in the mITT Population were analyzed at Day 85.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0551
	Comments
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	Mean Overall Patient Global Impression of Change (PGIC) Scores at Day 85
Description	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.
Time Frame	Day 85

Outcome Measure Data

Analysis Population Description

MITT Population. Only those participants with available data were analyzed. For participants with missing data at Day 85, the last available value has been used.

Arm/Group Title	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.	All participants receiving placebo, AVP-923-20, AVP-923-30, or AVP-923-45.
Measure Participants	43	45	46	45	179
Mean (Standard Deviation) [units on a scale]	3.58 (1.842)	4.42 (2.398)	3.70 (2.346)	3.64 (2.298)	3.84 (2.244)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AVP-923-20, AVP-923-30, AVP-923-45
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9207
	Comments	The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
	Method	ANCOVA
	Comments

13. Other Pre-specified Outcome

Title	Change From Baseline in Modified Ashworth Scale (MAS) Scores
Description	MAS is not considered as a true endpoint. MAS scores were assessed at Baseline only. Change from Baseline could not be calculated because data for the later timepoints was not collected.
Time Frame	Baseline; Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	AEs were collected up to Week 12.
Adverse Event Reporting Description	Treatment-emergent adverse events (AEs) were defined as those events with an onset that was anytime during the study and while on treatment, following the first dose of study drug on Day 1. AEs were reported for members of the Safety Population, comprising all participants who received at least one dose of the study drug. Safety analyses were performed based on the treatment participants actually received.
Arm/Group Title	Placebo		AVP-923-20		AVP-923-30		AVP-923-45
Arm/Group Description	Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.		Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.		Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.		Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
All Cause Mortality
	Placebo		AVP-923-20		AVP-923-30		AVP-923-45
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/54 (0%)		0/53 (0%)		0/53 (0%)
Serious Adverse Events
	Placebo		AVP-923-20		AVP-923-30		AVP-923-45
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/49 (2%)		1/54 (1.9%)		1/53 (1.9%)		2/53 (3.8%)
Ear and labyrinth disorders
Vertigo	0/49 (0%)		0/54 (0%)		0/53 (0%)		1/53 (1.9%)
Eye disorders
Diplopia	0/49 (0%)		0/54 (0%)		0/53 (0%)		1/53 (1.9%)
Gastrointestinal disorders
Duodenitis	1/49 (2%)		0/54 (0%)		0/53 (0%)		0/53 (0%)
Infections and infestations
Cellulitis	0/49 (0%)		1/54 (1.9%)		0/53 (0%)		0/53 (0%)
Pneumonia	0/49 (0%)		0/54 (0%)		1/53 (1.9%)		0/53 (0%)
Tonsillitis	0/49 (0%)		0/54 (0%)		0/53 (0%)		1/53 (1.9%)
Other (Not Including Serious) Adverse Events
	Placebo		AVP-923-20		AVP-923-30		AVP-923-45
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/49 (67.3%)		40/54 (74.1%)		43/53 (81.1%)		40/53 (75.5%)
Ear and labyrinth disorders
Tinnitus	0/49 (0%)		0/54 (0%)		1/53 (1.9%)		3/53 (5.7%)
Vertigo	0/49 (0%)		1/54 (1.9%)		1/53 (1.9%)		5/53 (9.4%)
Ear pain	0/49 (0%)		2/54 (3.7%)		0/53 (0%)		0/53 (0%)
Eye disorders
Vision blurred	0/49 (0%)		0/54 (0%)		3/53 (5.7%)		2/53 (3.8%)
Diplopia	0/49 (0%)		0/54 (0%)		1/53 (1.9%)		2/53 (3.8%)
Gastrointestinal disorders
Abdominal discomfort	1/49 (2%)		0/54 (0%)		2/53 (3.8%)		3/53 (5.7%)
Constipation	1/49 (2%)		3/54 (5.6%)		0/53 (0%)		3/53 (5.7%)
Diarrhoea	1/49 (2%)		2/54 (3.7%)		2/53 (3.8%)		3/53 (5.7%)
Nausea	7/49 (14.3%)		12/54 (22.2%)		10/53 (18.9%)		8/53 (15.1%)
Vomiting	0/49 (0%)		5/54 (9.3%)		2/53 (3.8%)		2/53 (3.8%)
Flatulence	0/49 (0%)		0/54 (0%)		2/53 (3.8%)		1/53 (1.9%)
General disorders
Fatigue	3/49 (6.1%)		3/54 (5.6%)		3/53 (5.7%)		3/53 (5.7%)
Asthenia	1/49 (2%)		2/54 (3.7%)		1/53 (1.9%)		2/53 (3.8%)
Malaise	0/49 (0%)		1/54 (1.9%)		2/53 (3.8%)		0/53 (0%)
Infections and infestations
Influenza	0/49 (0%)		1/54 (1.9%)		3/53 (5.7%)		2/53 (3.8%)
Nasopharyngitis	2/49 (4.1%)		1/54 (1.9%)		7/53 (13.2%)		4/53 (7.5%)
Upper respiratory tract infection	3/49 (6.1%)		1/54 (1.9%)		2/53 (3.8%)		2/53 (3.8%)
Urinary tract infection	3/49 (6.1%)		4/54 (7.4%)		5/53 (9.4%)		3/53 (5.7%)
Injury, poisoning and procedural complications
Excoriation	1/49 (2%)		0/54 (0%)		2/53 (3.8%)		0/53 (0%)
Fall	2/49 (4.1%)		2/54 (3.7%)		2/53 (3.8%)		0/53 (0%)
Investigations
Blood alkaline phosphatase increased	0/49 (0%)		2/54 (3.7%)		0/53 (0%)		0/53 (0%)
Gamma-glutamyltransferase increased	1/49 (2%)		2/54 (3.7%)		2/53 (3.8%)		1/53 (1.9%)
Musculoskeletal and connective tissue disorders
Muscle spasms	3/49 (6.1%)		1/54 (1.9%)		5/53 (9.4%)		0/53 (0%)
Musculoskeletal stiffness	0/49 (0%)		0/54 (0%)		0/53 (0%)		3/53 (5.7%)
Neck pain	0/49 (0%)		0/54 (0%)		3/53 (5.7%)		0/53 (0%)
Pain in extremity	4/49 (8.2%)		0/54 (0%)		2/53 (3.8%)		0/53 (0%)
Arthralgia	2/49 (4.1%)		1/54 (1.9%)		1/53 (1.9%)		1/53 (1.9%)
Back pain	0/49 (0%)		0/54 (0%)		2/53 (3.8%)		0/53 (0%)
Muscular weakness	0/49 (0%)		0/54 (0%)		2/53 (3.8%)		2/53 (3.8%)
Musculoskeletal chest pain	0/49 (0%)		0/54 (0%)		2/53 (3.8%)		1/53 (1.9%)
Sensation of heaviness	0/49 (0%)		0/54 (0%)		2/53 (3.8%)		0/53 (0%)
Nervous system disorders
Dizziness	4/49 (8.2%)		4/54 (7.4%)		9/53 (17%)		13/53 (24.5%)
Headache	6/49 (12.2%)		11/54 (20.4%)		14/53 (26.4%)		8/53 (15.1%)
Multiple sclerosis relapse	0/49 (0%)		2/54 (3.7%)		3/53 (5.7%)		3/53 (5.7%)
Muscle spasticity	2/49 (4.1%)		1/54 (1.9%)		2/53 (3.8%)		3/53 (5.7%)
Neuropathic pain	4/49 (8.2%)		2/54 (3.7%)		3/53 (5.7%)		0/53 (0%)
Somnolence	2/49 (4.1%)		5/54 (9.3%)		3/53 (5.7%)		5/53 (9.4%)
Hypoaesthesia	0/49 (0%)		2/54 (3.7%)		2/53 (3.8%)		1/53 (1.9%)
Migraine	1/49 (2%)		0/54 (0%)		0/53 (0%)		2/53 (3.8%)
Tremor	0/49 (0%)		0/54 (0%)		2/53 (3.8%)		1/53 (1.9%)
Uhthoff's phenomenon	2/49 (4.1%)		0/54 (0%)		0/53 (0%)		0/53 (0%)
Psychiatric disorders
Anxiety	1/49 (2%)		1/54 (1.9%)		3/53 (5.7%)		0/53 (0%)
Depression	1/49 (2%)		0/54 (0%)		3/53 (5.7%)		2/53 (3.8%)
Insomnia	1/49 (2%)		3/54 (5.6%)		2/53 (3.8%)		2/53 (3.8%)
Respiratory, thoracic and mediastinal disorders
Cough	0/49 (0%)		0/54 (0%)		0/53 (0%)		2/53 (3.8%)
Vascular disorders
Hot flush	2/49 (4.1%)		0/54 (0%)		0/53 (0%)		0/53 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.