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Clinical Trial Results:
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

Summary
EudraCT number	2011-002178-22
Trial protocol	ES CZ PL GB
Global end of trial date	26 Sep 2013

Results information
Results version number	v1(current)
This version publication date	02 Jan 2021
First version publication date	02 Jan 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

11-AVR-130

ISRCTN number

US NCT number

NCT01324232

WHO universal trial number (UTN)

Sponsor organisation name

Avanir Pharmaceuticals, Inc.

Sponsor organisation address

30 Enterprise, Suite 400, Aliso Viejo, California, United States, 92656

Public contact

Clinical Trial Information Desk, Avanir Pharmaceuticals, Inc., 1 949-268-1167, study11AVR130@avanir.com

Scientific contact

Clinical Trial Information Desk, Avanir Pharmaceuticals, Inc., 1 949-268-1167, study11AVR130@avanir.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Nov 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

The objectives of the study are to evaluate the safety, tolerability, and efficacy of 3 doses of AVP-923 capsules containing either 45 mg DM and 10 mg Q (AVP-923-45) or 30 mg DM 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 patients with multiple sclerosis (MS) over a 12-week period.

Protection of trial subjects

Ethics committees met the guidelines set out by the Food and Drug Administration (FDA) and conformed to local laws and customs where appropriate. Written institutional review board (IRB) approval for the protocol and the signed informed consent form (ICF) were obtained and transmitted to Avanir Pharmaceuticals, Inc. or their representative before the study was initiated. The IRB was informed of and approved all protocol amendments. Modifications that eliminated an apparent immediate hazard to patients did not require preapproval by the IRB/IEC. Standards for Good Clinical Practice, as outlined by regional regulations, were adhered to for all study-based procedures. The investigator ensured that this study was conducted in full conformance with the laws and regulations of the United States. Informed consent followed the principles outlined in the current version of the Helsinki Declaration. Each patient found to be eligible for the study was properly informed of the purpose of the study. The patient was alerted to any anticipated adverse event (AE) that may be encountered with the study drug. A signed ICF was obtained from all patients (or their authorized representative if enrolled prior to Amendment 2 of the protocol) prior to patient entry into this study. Patients were provided with a copy of their signed ICF (except for patients enrolled prior to Amendment 1 of the protocol).

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Sep 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 31

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

Czech Republic: 48

Country: Number of subjects enrolled

United States: 112

Country: Number of subjects enrolled

Argentina: 8

Worldwide total number of subjects

209

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

198

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

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).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm 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.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral capsule; once daily and twice daily

AVP-923-20

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

AVP-923

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral capsule; once daily and twice daily

AVP-923-30

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

AVP-923

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral capsule; once daily and twice daily

AVP-923-45

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

AVP-923

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral capsule; once daily and twice daily

Number of subjects in period 1	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Started	49	53	54	53
Completed	44	42	41	42
Not completed	5	11	13	11
Consent withdrawn by subject	-	3	4	-
Adverse event, non-fatal	2	5	6	6
Other	2	2	2	2
Intercurrent illness	-	-	-	1
Patient refused medication	-	1	-	-
Lost to follow-up	1	-	-	-
Missing	-	-	1	-
Protocol deviation	-	-	-	2

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

AVP-923-20

Reporting group description

Reporting group title

AVP-923-30

Reporting group description

Reporting group title

AVP-923-45

Reporting group description

Reporting group values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Number of subjects	49	53	54	53	209
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	49.7 ( 8.41 )	47.2 ( 9.20 )	49.1 ( 11.21 )	48.1 ( 13.04 )	-
Gender categorical
Units: Subjects
Female	40	46	42	41	169
Male	9	7	12	12	40
Race/Ethnicity, Customized
Units: Subjects
Caucasian	43	46	49	48	186
Black or African American	3	4	5	4	16
Asian	1	0	0	0	1
Hispanic or Latino	2	3	0	1	6

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

AVP-923-20

Reporting group description

Reporting group title

AVP-923-30

Reporting group description

Reporting group title

AVP-923-45

Reporting group description

Subject analysis set title

Placebo

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Participants received one matching placebo capsule containing 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.

Subject analysis set title

AVP-923-20

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

AVP-923-30

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

AVP-923-45

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Total

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All participants receiving placebo, AVP-923-20, AVP-923-30, or AVP-923-45.

Subject analysis set title

AVP-923-20 and AVP-923-30

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

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.

Subject analysis set title

AVP-923-30 and AVP-923-45

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

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.

Subject analysis set title

All AVP-923

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All participants receiving AVP-923-20, AVP-923-30, or AVP-923-45.

Primary: Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

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End point title

Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

End point description

The association between the DM plasma concentration and the change from Baseline (BL) PRS score to the average PRS score during Days 57 through 84 was measured. The PRS requires participants (par.) 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 describes their pain on average over the past 12 hours. Baseline (BL) PRS was defined as the average of the PRS scores in the last 7 days collected prior to the BL visit. Post-BL PRS is the average of the Day 57 through 84 values. For par. who did not have any PRS scores during Days 57 through 84, the average of the last 7 available post-BL PRS scores was used. Change from BL was calculated as the post-BL score minus the BL score. Modified Intention-To-Treat (MITT) Population: all par. in the ITT Population (randomized participants) who received >=1 dose of study drug, provided a BL PRS score, and had >=1 post-BL PRS assessment. 999=data not available.

End point type

Primary

End point timeframe

Baseline; Days 57 through 84

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Number of subjects analysed	49 ^[1]	53 ^[2]	54 ^[3]	53 ^[4]	209 ^[5]
Units: units on a scale
median (full range (min-max))
Change from BL in PRS Scores, n=49,53,54,53,209	-1.821 (-7.86 to 2.06)	-2.143 (-7.60 to 5.71)	-2.650 (-6.54 to 3.00)	-1.679 (-6.79 to 2.00)	-2.000 (-7.86 to 5.71)
DM Plasma Concentration, n=0,43,35,45,133	999 (999 to 999)	4.019 (2.38 to 4.84)	4.493 (3.27 to 5.55)	4.758 (-1.61 to 5.81)	4.394 (-1.61 to 5.81)

Notes
[1] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[2] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[3] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[4] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[5] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)

Statistical Analysis 1

Statistical analysis description

The null hypothesis was 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.

Comparison groups

AVP-923-20 v AVP-923-30 v Placebo v AVP-923-45

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9827

Method

t-test, 2-sided

Confidence interval

Secondary: Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

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End point title

Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

End point description

The PRS requires 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 describes 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 is 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. PRS score change from baseline to Days 57-84 was the dependent variable, treatment group was a fixed effect, and the baseline PRS score was a covariate.

End point type

Secondary

End point timeframe

Baseline; Days 57 through 84

End point values	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
Number of subjects analysed	49 ^[6]	53 ^[7]	54 ^[8]	53 ^[9]	107 ^[10]	107 ^[11]	160 ^[12]
Units: units on a scale
least squares mean (standard error)	-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 )

Notes
[6] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[7] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[8] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[9] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[10] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[11] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[12] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)

Statistical Analysis 1

Statistical analysis description

Overall P value tested the hypothesis of no treatment effect.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8869

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9381

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

0.87

Variability estimate

Standard error of the mean

Dispersion value

0.46

Statistical Analysis 3

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4128

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-1.28

upper limit

0.53

Variability estimate

Standard error of the mean

Dispersion value

0.46

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9427

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.94

Variability estimate

Standard error of the mean

Dispersion value

0.461

Statistical Analysis 5

Comparison groups

Placebo v AVP-923-20 and AVP-923-30

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6075

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.58

Variability estimate

Standard error of the mean

Dispersion value

0.401

Statistical Analysis 6

Comparison groups

Placebo v AVP-923-30 and AVP-923-45

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.669

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.96

upper limit

0.62

Variability estimate

Standard error of the mean

Dispersion value

0.402

Statistical Analysis 7

Comparison groups

Placebo v All AVP-923

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7394

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.62

Variability estimate

Standard error of the mean

Dispersion value

0.38

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Scores

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End point title

Change From Baseline in Fatigue Severity Scale (FSS) Scores

End point description

The FSS questionnaire contains 9 statements that attempt 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 is 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.” The total score is computed as the sum of the sub-scores for all 9 statements; a higher score indicates increasing fatigue. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit have been included in the analysis. FSS change from BL was the dependent variable, treatment group was a fixed effect, and the BL FSS was a covariate.

End point type

Secondary

End point timeframe

Baseline; Days 57 through 84

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Number of subjects analysed	48 ^[13]	52 ^[14]	54 ^[15]	53 ^[16]
Units: units on a scale
least squares mean (standard error)	-3.32 ( 1.742 )	-2.00 ( 1.680 )	-6.32 ( 1.642 )	-2.12 ( 1.662 )

Notes
[13] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[14] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[15] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[16] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9731

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

-3.45

upper limit

6.09

Variability estimate

Standard error of the mean

Dispersion value

2.42

Statistical Analysis 3

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.72

upper limit

1.72

Variability estimate

Standard error of the mean

Dispersion value

2.394

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.54

upper limit

5.95

Variability estimate

Standard error of the mean

Dispersion value

2.408

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

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End point title

Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

End point description

The EDSS is a method of quantifying disability in participants with MS. It is based on neurological examination of 8 functional systems (FS) (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other) that allows neurologists to assign a FS score to each of these systems. Neurological findings in each FS are scored on a scale of 0 (low level of problems) to 5 (high level of problems). The “other” category is not rated numerically but measures disability related to a particular issue, like motor loss. A total EDSS score is then calculated on a scale of 0 (normal) to 10 (death from MS). The total EDSS score is determined by 2 factors: gait and FS scores. A higher score indicates greater disability. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Days 22 and 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Number of subjects analysed	49 ^[17]	54 ^[18]	53 ^[19]	53 ^[20]	209 ^[21]
Units: units on a scale
arithmetic mean (standard deviation)
Day 22, n=46, 41, 42, 45, 174	-0.1 ( 0.35 )	-0.1 ( 0.56 )	-0.2 ( 0.67 )	-0.0 ( 0.63 )	-0.1 ( 0.56 )
Day 85, n=48, 51, 49, 52, 200	-0.1 ( 0.75 )	-0.1 ( 0.67 )	-0.1 ( 0.46 )	0.0 ( 0.58 )	-0.1 ( 0.62 )

Notes
[17] - Safety Population: all participants who received at least 1 dose of study drug
[18] - Safety Population: all participants who received at least 1 dose of study drug
[19] - Safety Population: all participants who received at least 1 dose of study drug
[20] - Safety Population: all participants who received at least 1 dose of study drug
[21] - Safety Population: all participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

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End point title

Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

End point description

The MSIS-29 is an instrument measuring the physical (20 items) and psychological (9 items) impact of MS from the participant' perspective and is 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 is calculated as the sum of the sub-scores for all 29 questions, with lower scores indicating better quality of life. Baseline is defined as last non-missing measurement prior to dosing. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. For participants with missing data at Day 85, the last available value has been used. MSIS change from Baseline to Day 85 was the dependent variable, treatment group was a fixed effect, and the Baseline MSIS was a covariate.

End point type

Secondary

End point timeframe

Baseline; Day 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Number of subjects analysed	49 ^[22]	53 ^[23]	54 ^[24]	53 ^[25]
Units: units on a scale
least squares mean (standard error)	-4.84 ( 2.651 )	-4.34 ( 2.551 )	-6.50 ( 2.526 )	-1.41 ( 2.550 )

Notes
[22] - mITT Population: Analysis was based on the randomized treatment assigned
[23] - mITT Population: Analysis was based on the randomized treatment assigned
[24] - mITT Population: Analysis was based on the randomized treatment assigned
[25] - mITT Population: Analysis was based on the randomized treatment assigned

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4778

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-6.76

upper limit

7.74

Variability estimate

Standard error of the mean

Dispersion value

3.676

Statistical Analysis 3

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-1.67

Confidence interval

level

95%

sides

2-sided

lower limit

-8.89

upper limit

5.56

Variability estimate

Standard error of the mean

Dispersion value

3.663

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

3.43

Confidence interval

level

95%

sides

2-sided

lower limit

-3.83

upper limit

10.68

Variability estimate

Standard error of the mean

Dispersion value

3.681

Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

Top of page

End point title

Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

End point description

The PSQI is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month time interval. A total of 19 individual items generate 7 component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 (no difficulty) to 3 (severe difficulty). The sum of the scores for the 7 components yields 1 global score (from 0 to 21). A higher PSQI score indicates worse quality of sleep. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit were included in the analysis. For participants with missing data at Day 85, the last available value was used. PSQI change from BL was the dependent variable, treatment group was a fixed effect, and the BL PQIS was a covariate.

End point type

Secondary

End point timeframe

Baseline; Day 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Number of subjects analysed	49 ^[26]	53 ^[27]	54 ^[28]	53 ^[29]
Units: units on a scale
least squares mean (standard error)	-0.51 ( 0.490 )	-1.02 ( 0.471 )	-1.36 ( 0.467 )	-1.71 ( 0.472 )

Notes
[26] - mITT Population: Analysis was based on the randomized treatment assigned
[27] - mITT Population: Analysis was based on the randomized treatment assigned
[28] - mITT Population: Analysis was based on the randomized treatment assigned
[29] - mITT Population: Analysis was based on the randomized treatment assigned

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0685

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.85

upper limit

0.83

Variability estimate

Standard error of the mean

Dispersion value

0.68

Statistical Analysis 3

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.85

Confidence interval

level

95%

sides

2-sided

lower limit

-2.19

upper limit

0.48

Variability estimate

Standard error of the mean

Dispersion value

0.677

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.54

upper limit

0.15

Variability estimate

Standard error of the mean

Dispersion value

0.681

Secondary: Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

Top of page

End point title

Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

End point description

The MSNQ is a self-reporting, 15-item questionnaire developed 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 is calculated as the sum of the sub-scores for all 15 questions and thus ranges from 0 to 60. A higher score indicates greater impairment. Baseline is defined as last non-missing measurement prior to dosing. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. 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. MSNQ change from Baseline to Day 85 was the dependent variable, treatment group was a fixed effect, and the Baseline MSNQ was a covariate.

End point type

Secondary

End point timeframe

Baseline; Day 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Number of subjects analysed	48 ^[30]	52 ^[31]	54 ^[32]	53 ^[33]
Units: units on a scale
least squares mean (standard error)	-0.99 ( 1.058 )	-1.48 ( 1.020 )	-1.88 ( 0.998 )	0.47 ( 1.006 )

Notes
[30] - mITT Population: Analysis was based on the randomized treatment assigned
[31] - mITT Population: Analysis was based on the randomized treatment assigned
[32] - mITT Population: Analysis was based on the randomized treatment assigned
[33] - mITT Population: Analysis was based on the randomized treatment assigned

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.

Comparison groups

AVP-923-20 v Placebo v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4201

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

2.41

Variability estimate

Standard error of the mean

Dispersion value

1.473

Statistical Analysis 3

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.76

upper limit

1.97

Variability estimate

Standard error of the mean

Dispersion value

1.454

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

-1.42

upper limit

4.34

Variability estimate

Standard error of the mean

Dispersion value

1.46

Secondary: Change From Baseline in Beck Depression Inventory (BDI-II) Scores

Top of page

End point title

Change From Baseline in Beck Depression Inventory (BDI-II) Scores

End point description

The BDI-II is a 21-item, self-reported instrument intended to assess the existence and severity of symptoms of depression. Each item corresponds to a symptom of depression and is scored on a 4-point scale, ranging from 0 to 3. Participants are asked to consider each statement as it relates to the way they have felt for the past 2 weeks. Each of the 21 items is summed to give a single score (ranging from 0 to 63). A total score of 0 to 13 indicates minimal depression, a score of 14 to 19 indicates mild depression, a score of 20 to 28 indicates moderate depression, and a score of 29 to 63 indicates severe depression. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used.

End point type

Secondary

End point timeframe

Baseline; Day 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Number of subjects analysed	49 ^[34]	53 ^[35]	54 ^[36]	53 ^[37]
Units: units on a scale
least squares mean (standard error)	0.83 ( 0.868 )	-0.26 ( 0.835 )	0.21 ( 0.828 )	1.15 ( 0.837 )

Notes
[34] - mITT Population: Analysis was based on the randomized treatment assigned
[35] - mITT Population: Analysis was based on the randomized treatment assigned
[36] - mITT Population: Analysis was based on the randomized treatment assigned
[37] - mITT Population: Analysis was based on the randomized treatment assigned

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8068

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.47

upper limit

1.28

Variability estimate

Standard error of the mean

Dispersion value

1.205

Statistical Analysis 3

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-2.99

upper limit

1.74

Variability estimate

Standard error of the mean

Dispersion value

1.2

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-2.07

upper limit

2.69

Variability estimate

Standard error of the mean

Dispersion value

1.207

Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

Top of page

End point title

Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

End point description

The SDMT assesses organic cerebral dysfunction in both children (8 years and older) and adults. The SDMT involves a simple substitution task that normal participants can easily perform. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. The SDMT score is the total correct response (not counting errors) in 90 seconds and ranges from 0 to 110. Lower scores indicate increased dysfunction. Baseline is defined as last non-missing measurement prior to dosing. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. 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. SDMT change from Baseline to Day 85 was the dependent variable, treatment group was a fixed effect, and the Baseline SDMT was a covariate.

End point type

Secondary

End point timeframe

Baseline; Day 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Number of subjects analysed	48 ^[38]	52 ^[39]	54 ^[40]	53 ^[41]
Units: units on a scale
least squares mean (standard error)
Total correct responses, oral; n=11, 13, 20, 14	0.59 ( 2.045 )	2.96 ( 1.881 )	1.91 ( 1.525 )	2.06 ( 1.809 )
Total correct responses, written; n=37, 39, 34, 39	1.85 ( 1.111 )	3.62 ( 1.086 )	0.16 ( 1.158 )	0.20 ( 1.083 )

Notes
[38] - mITT Population: Analysis was based on the randomized treatment assigned
[39] - mITT Population: Analysis was based on the randomized treatment assigned
[40] - mITT Population: Analysis was based on the randomized treatment assigned
[41] - mITT Population: Analysis was based on the randomized treatment assigned

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect. Oral responses.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6315

Method

ANCOVA

Confidence interval

Statistical Analysis 2

Statistical analysis description

Oral responses

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

2.37

Confidence interval

level

95%

sides

2-sided

lower limit

-3.19

upper limit

7.93

Variability estimate

Standard error of the mean

Dispersion value

2.772

Statistical Analysis 3

Statistical analysis description

Oral responses

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

-3.83

upper limit

6.45

Variability estimate

Standard error of the mean

Dispersion value

2.562

Statistical Analysis 4

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

-4.01

upper limit

6.94

Variability estimate

Standard error of the mean

Dispersion value

2.728

Statistical Analysis 5

Statistical analysis description

P-value presented tests the hypothesis for overall treatment effect versus no treatment effect. Written responses.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1485

Method

ANCOVA

Confidence interval

Statistical Analysis 6

Statistical analysis description

Written responses

Comparison groups

Placebo v AVP-923-20

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

1.77

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

4.85

Variability estimate

Standard error of the mean

Dispersion value

1.558

Statistical Analysis 7

Statistical analysis description

Written responses

Comparison groups

Placebo v AVP-923-30

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-1.68

Confidence interval

level

95%

sides

2-sided

lower limit

-4.86

upper limit

1.49

Variability estimate

Standard error of the mean

Dispersion value

1.605

Statistical Analysis 8

Statistical analysis description

Written responses

Comparison groups

Placebo v AVP-923-45

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-1.65

Confidence interval

level

95%

sides

2-sided

lower limit

-4.71

upper limit

1.41

Variability estimate

Standard error of the mean

Dispersion value

1.549

Secondary: Mean Numerical Rating Scale (NRS) Scores

Top of page

End point title

Mean Numerical Rating Scale (NRS) Scores

End point description

The NRS is an 11-point scale for participant self-reporting of pain. Scores range from 0 (no spasticity) to 10 (worst possible spasticity). 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.

End point type

Secondary

End point timeframe

Baseline; Days 22, 50, and 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Number of subjects analysed	45 ^[42]	49 ^[43]	49 ^[44]	47 ^[45]	190 ^[46]
Units: units on a scale
arithmetic mean (standard deviation)
Day 22, n=42, 39, 37, 40, 158	3.29 ( 2.717 )	3.56 ( 3.016 )	3.41 ( 2.723 )	3.90 ( 2.649 )	3.54 ( 2.762 )
Day 50, n=42, 37, 36, 37, 152	3.24 ( 2.721 )	2.89 ( 2.633 )	4.06 ( 2.888 )	3.54 ( 2.364 )	3.42 ( 2.666 )
Day 85, n=44, 48, 46, 47, 185	3.66 ( 2.869 )	3.13 ( 3.085 )	3.87 ( 2.825 )	3.36 ( 2.666 )	3.50 ( 2.857 )

Notes
[42] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[43] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[44] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[45] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[46] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1404 ^[47]

Method

t-test, 2-sided

Confidence interval

Notes
[47] - Day 22

Statistical Analysis 2

Statistical analysis description

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.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0805 ^[48]

Method

t-test, 2-sided

Confidence interval

Notes
[48] - Day 50

Statistical Analysis 3

Statistical analysis description

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.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0551 ^[49]

Method

t-test, 2-sided

Confidence interval

Notes
[49] - Day 85

Secondary: Summary of Patient Global Impression of Change (PGIC) Scores

Top of page

End point title

Summary of Patient Global Impression of Change (PGIC) Scores

End point description

The PGIC is 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). Only participants with a value at 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.

End point type

Secondary

End point timeframe

Day 85

End point values	Placebo	AVP-923-20	AVP-923-30	AVP-923-45	Total
Number of subjects analysed	43 ^[50]	45 ^[51]	46 ^[52]	45 ^[53]	179 ^[54]
Units: units on a scale
arithmetic mean (standard deviation)	3.58 ( 1.842 )	4.42 ( 2.398 )	3.70 ( 2.346 )	3.64 ( 2.298 )	3.84 ( 2.244 )

Notes
[50] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[51] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[52] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[53] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
[54] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)

Statistical Analysis 1

Statistical analysis description

The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.

Comparison groups

Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9207

Method

ANCOVA

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment-emergent adverse events (AEs) are 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 collected up to Week 12.

Adverse event reporting additional description

AEs are reported for members of the Safety Population, comprising all participants who received at least one dose of study drug. Safety analyses were performed based on the treatment participants actually received.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

Placebo

Reporting group description

Reporting group title

AVP-923-20

Reporting group description

Reporting group title

AVP-923-30

Reporting group description

Reporting group title

AVP-923-45

Reporting group description

Serious adverse events	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	2 / 53 (3.77%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Duodenitis
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Placebo	AVP-923-20	AVP-923-30	AVP-923-45
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 49 (67.35%)	40 / 54 (74.07%)	43 / 53 (81.13%)	40 / 53 (75.47%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibroadenoma of breast
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Vascular disorders
Flushing
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Haematoma
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	4
Hot flush
subjects affected / exposed	2 / 49 (4.08%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	2	0	0	0
Hypotension
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Peripheral coldness
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Venous insufficiency
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 49 (2.04%)	2 / 54 (3.70%)	1 / 53 (1.89%)	2 / 53 (3.77%)
occurrences all number	1	3	1	2
Chest discomfort
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	0	3	0
Chills
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Fatigue
subjects affected / exposed	3 / 49 (6.12%)	3 / 54 (5.56%)	3 / 53 (5.66%)	3 / 53 (5.66%)
occurrences all number	3	3	4	4
Feeling cold
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Feeling jittery
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Gait disturbance
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Malaise
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	0	1	2	0
Oedema peripheral
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	1	1	1	1
Pain
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	1	1	1
Product taste abnormal
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Metrorrhagia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Ovarian cyst
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Bronchial hyperreactivity
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Cough
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	2 / 53 (3.77%)
occurrences all number	0	0	0	2
Dyspnoea
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	1	3	0
Oropharyngeal pain
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Sinus congestion
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	1	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Anxiety
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	3 / 53 (5.66%)	0 / 53 (0.00%)
occurrences all number	1	1	4	0
Bruxism
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Confusional state
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Depression
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	3 / 53 (5.66%)	2 / 53 (3.77%)
occurrences all number	1	0	3	2
Hallucination
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Insomnia
subjects affected / exposed	1 / 49 (2.04%)	3 / 54 (5.56%)	2 / 53 (3.77%)	2 / 53 (3.77%)
occurrences all number	1	3	2	2
Libido decreased
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Stress
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	1	1	1	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	1	1	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 49 (0.00%)	2 / 54 (3.70%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	2	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	0	1	2	0
Blood sodium decreased
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	0	0	2	1
Electrocardiogram ST segment depression
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 49 (2.04%)	2 / 54 (3.70%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	1	2	2	1
Heart rate irregular
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	1	1	0
Urine analysis abnormal
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Weight increased
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
White blood cells urine positive
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Burns second degree
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Contusion
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	2	0	0	1
Excoriation
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	1	0	2	0
Fall
subjects affected / exposed	2 / 49 (4.08%)	2 / 54 (3.70%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	2	2	3	0
Hand fracture
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Joint injury
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Laceration
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Ligament sprain
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Overdose
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Post-traumatic pain
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Sunburn
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Tooth fracture
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Bradycardia
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Bundle branch block left
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	2	0	0
Palpitations
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	1	1	0
Tachycardia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Burning sensation
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	1	1	0
Cervical cord compression
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Clumsiness
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Cognitive disorder
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Demyelination
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Disturbance in attention
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Dizziness
subjects affected / exposed	4 / 49 (8.16%)	4 / 54 (7.41%)	9 / 53 (16.98%)	13 / 53 (24.53%)
occurrences all number	4	6	13	22
Dysgeusia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Extensor plantar response
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Headache
subjects affected / exposed	6 / 49 (12.24%)	11 / 54 (20.37%)	14 / 53 (26.42%)	8 / 53 (15.09%)
occurrences all number	9	20	22	23
Hemiparesis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Hyperreflexia
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Hypertonia
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Hypoaesthesia
subjects affected / exposed	0 / 49 (0.00%)	2 / 54 (3.70%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	0	2	2	2
Lethargy
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	0	1	0
Loss of consciousness
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Memory impairment
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	0	1	0
Mental impairment
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Migraine
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	2 / 53 (3.77%)
occurrences all number	1	0	0	3
Multiple sclerosis relapse
subjects affected / exposed	0 / 49 (0.00%)	2 / 54 (3.70%)	3 / 53 (5.66%)	3 / 53 (5.66%)
occurrences all number	0	2	3	3
Muscle spasticity
subjects affected / exposed	2 / 49 (4.08%)	1 / 54 (1.85%)	2 / 53 (3.77%)	3 / 53 (5.66%)
occurrences all number	3	1	2	4
Neuralgia
subjects affected / exposed	4 / 49 (8.16%)	2 / 54 (3.70%)	3 / 53 (5.66%)	0 / 53 (0.00%)
occurrences all number	5	2	3	0
Paraesthesia
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Restless legs syndrome
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Sciatica
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Sinus headache
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	1	1	0
Somnolence
subjects affected / exposed	2 / 49 (4.08%)	5 / 54 (9.26%)	3 / 53 (5.66%)	5 / 53 (9.43%)
occurrences all number	2	6	3	5
Syncope
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Tremor
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	0	0	2	2
Trigeminal neuralgia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Uhthoff's phenomenon
subjects affected / exposed	2 / 49 (4.08%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	2	0	0	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Lymphopenia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 49 (0.00%)	2 / 54 (3.70%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	2	0	0
Tinnitus
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	3 / 53 (5.66%)
occurrences all number	0	0	1	3
Vertigo
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	5 / 53 (9.43%)
occurrences all number	0	1	2	5
Eye disorders
Diplopia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	2 / 53 (3.77%)
occurrences all number	0	0	1	2
Dry eye
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Eye irritation
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Eye pain
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Eyelid oedema
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Uveitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	3 / 53 (5.66%)	2 / 53 (3.77%)
occurrences all number	0	0	3	3
Vitreous floaters
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	2 / 53 (3.77%)	3 / 53 (5.66%)
occurrences all number	1	0	2	3
Abdominal distension
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Constipation
subjects affected / exposed	1 / 49 (2.04%)	3 / 54 (5.56%)	0 / 53 (0.00%)	3 / 53 (5.66%)
occurrences all number	1	3	0	4
Crohn's disease
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Diarrhoea
subjects affected / exposed	1 / 49 (2.04%)	2 / 54 (3.70%)	2 / 53 (3.77%)	3 / 53 (5.66%)
occurrences all number	1	2	3	4
Dry mouth
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	2 / 53 (3.77%)
occurrences all number	1	1	1	2
Duodenitis
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Dyspepsia
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	1	1	1	1
Dysphagia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Faecal incontinence
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Flatulence
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	0	0	2	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Nausea
subjects affected / exposed	7 / 49 (14.29%)	12 / 54 (22.22%)	10 / 53 (18.87%)	8 / 53 (15.09%)
occurrences all number	7	16	10	11
Periodontitis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Toothache
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	2	1	0
Vomiting
subjects affected / exposed	0 / 49 (0.00%)	5 / 54 (9.26%)	2 / 53 (3.77%)	2 / 53 (3.77%)
occurrences all number	0	6	2	3
Chest pain
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Skin and subcutaneous tissue disorders
Cold sweat
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	2	1	0	0
Decubitus ulcer
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Ecchymosis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Eczema
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	1	2	2
Pruritus
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	1	0	0
Rash
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Renal pain
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	1	0	0
Urinary incontinence
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Urinary retention
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Endocrine disorders
Early menarche
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 49 (4.08%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	3	1	1	1
Back pain
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	0	0	2	0
Bone pain
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	2	0	0
Costochondritis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Muscle spasms
subjects affected / exposed	3 / 49 (6.12%)	1 / 54 (1.85%)	5 / 53 (9.43%)	0 / 53 (0.00%)
occurrences all number	4	1	6	0
Muscle tightness
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	2	0	0
Muscular weakness
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	2 / 53 (3.77%)
occurrences all number	0	0	2	4
Musculoskeletal chest pain
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	0	0	2	1
Musculoskeletal discomfort
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	0	1	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	3 / 53 (5.66%)
occurrences all number	0	0	0	3
Myalgia
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	1	0	4	1
Neck pain
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	3 / 53 (5.66%)	0 / 53 (0.00%)
occurrences all number	0	0	3	0
Pain in extremity
subjects affected / exposed	4 / 49 (8.16%)	0 / 54 (0.00%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	4	0	2	0
Pain in jaw
subjects affected / exposed	1 / 49 (2.04%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	1	0	0
Plantar fasciitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Rotator cuff syndrome
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Sensation of heaviness
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	0	0	2	0
Infections and infestations
Asymptomatic bacteriuria
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Bronchitis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	1	1	1
Cellulitis
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	0	1	0	0
Cystitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Ear infection
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Fungal infection
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	0	0	1	1
Gastrointestinal viral infection
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	1	0
Herpes zoster
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Influenza
subjects affected / exposed	0 / 49 (0.00%)	1 / 54 (1.85%)	3 / 53 (5.66%)	2 / 53 (3.77%)
occurrences all number	0	1	3	2
Laryngitis
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	1	0	0	0
Nasopharyngitis
subjects affected / exposed	2 / 49 (4.08%)	1 / 54 (1.85%)	7 / 53 (13.21%)	4 / 53 (7.55%)
occurrences all number	2	1	7	4
Oral candidiasis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Oral herpes
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	1	0	0	1
Pneumonia
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	0	0	2	0
Sinusitis
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	1	0	0	1
Subcutaneous abscess
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Tonsillitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Tooth infection
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	2	0	0	1
Upper respiratory tract infection
subjects affected / exposed	3 / 49 (6.12%)	1 / 54 (1.85%)	2 / 53 (3.77%)	2 / 53 (3.77%)
occurrences all number	3	1	2	2
Urinary tract infection
subjects affected / exposed	3 / 49 (6.12%)	4 / 54 (7.41%)	5 / 53 (9.43%)	3 / 53 (5.66%)
occurrences all number	3	5	5	3
Viral infection
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	1	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences all number	1	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 49 (2.04%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	1	0	0	1
Increased appetite
subjects affected / exposed	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences all number	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

20 Jun 2011

•Text was added to further clarify the diagnosis of and the eligibility criteria for central neuropathic pain. • Participants with a resting respiratory rate of >20 breaths/minute were ineligible for the study. • A posttreatment, safety follow-up visit was added to the study at Week 13 (Visit 6 [Day 92]). • Early termination was added as 1 of the time points when participants were to return unused study drug to the clinic. • Text was added to clarify the timing, calculation, and review of Pain Rating Scale (PRS) scores in the participants’ diaries. • It was clarified that patient diaries would be reviewed to determine eligibility. • The Expanded Disability Status Scale (EDSS) was changed from an efficacy assessment to a safety assessment. • The Symbol Digit Modalities Test (SDMT) was added as an efficacy assessment. • It was clarified that participants must complete a 1-week washout period for analgesic medications (when applicable), except for acetaminophen in doses up to 2600 milligrams per day. • Text was added to inclusion criteria to specify that dose adjustment may be needed for selective serotonin reuptake inhibitors SSRIs that are CYP2D6 substrates when coadministered with quinidine. • “Physical, psychological, and behavioral” were added as descriptors of unintended change to the definition of an adverse event. • Text was added specifying that any newly reported adverse experience, after receiving the last dose of study drug and up until 30 days after receiving the last dose of study drug, would be followed up until resolved. • Pregnancy was added to the list of reasons why participants may be withdrawn from the study. • It was specified that follow-up of laboratory test results should continue until test values return to the participant’s normal baseline (pretreatment) range. • The process and procedures for monitoring compliance with the study protocol and the overall quality of data collected was clarified.

15 Dec 2011

• The total number of sites was increased from approximately 65 sites to approximately 90 sites. • Eligibility criteria were updated. • Text was added stating that a sponsor may withdraw a participant from the study for administrative reasons. • The Modified Ashworth Scale (MAS), Patient Global Impression of Change (PGIC), and Numerical Rating Scale (NRS) were added as efficacy assessments. • A definition for compliance was added. • A modified Intent-to-Treat (MITT) population was added to the analysis populations. • An additional pharmacokinetic sample collection was added to Visit 4 (Day 50). • Text was removed stating that the study drug could be administered by the caregiver and that the caregiver could complete the participant’s diaries. • The stabilization period for multiple sclerosis (MS) disease-modifying therapy was reduced to at least 2 months before randomization from at least 3 months before randomization. • Text was added stating that oral steroids at a stable dose prior to randomization were allowed as long as the dose remained unchanged during the study. • Acetaminophen up to 2600 mg/day was replaced with ibuprofen up to 800 mg/day as a permitted rescue pain medication. • It was clarified that participants should not begin recording their daily pain score until the 1-week washout period was completed, if applicable. • Informants (i.e., a person having contact with the participant at least 3 times a week) could not complete the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ). • It was clarified that an MS relapse or acute exacerbation was defined as symptoms causing significant change in functional ability or in sensory function. • Randomization was stratified by geographic region instead of by center. Dynamic allocation was handled by interactive voice response system (IVRS). • Text in the introduction was reorganized, deleted, and added. • Records of all investigational product dispensing were in the eCRF.

24 Apr 2013

• The sample size was updated to 200 patients from 400 participants. • Due to the decreased sample size, the primary efficacy endpoint was updated from the change from baseline PRS scores to an assessment of the correlation between DM Cmax and change from baseline PRS scores. The key secondary efficacy endpoint changed from change in Fatigue Severity Scores (FSS) to the change from baseline PRS scores. The change in FSS scores was still included as an additional secondary endpoint. • Participants who participated in an interventional clinical study within the past 30 days were excluded from participating in the study; the previous version stated that participating in any clinical study was exclusionary. • Participants with evidence of uncontrolled diabetes based on HbA1c >53 millimoles/mole (mmol/mol) (>7.0%) were excluded from the study; in previous versions, participants with HbA1c <53 mmol/mol (>7.0%) were excluded from participating. • Height and weight were added to the vital sign measurements. • It was clarified that AEs reported after receiving the last dose of study drug would be followed up until resolution or until stabilization of the event had occurred. • Text stating that participant instructions would be reviewed in person and that written instructions would be provided to the participant or their caregiver was removed. • It was clarified that concomitant medication use should not be entered in the patient diary card, as this information was captured in the electronic Case Report Form.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

Primary: Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

Secondary: Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

Secondary: Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Scores

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Scores

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

Secondary: Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

Secondary: Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

Secondary: Change From Baseline in Beck Depression Inventory (BDI-II) Scores

Secondary: Change From Baseline in Beck Depression Inventory (BDI-II) Scores

Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

Secondary: Mean Numerical Rating Scale (NRS) Scores

Secondary: Mean Numerical Rating Scale (NRS) Scores

Secondary: Summary of Patient Global Impression of Change (PGIC) Scores

Secondary: Summary of Patient Global Impression of Change (PGIC) Scores

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Bulgaria
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Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
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Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

Primary: Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

Secondary: Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

Secondary: Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Scores

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Scores

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

Secondary: Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

Secondary: Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

Secondary: Change From Baseline in Beck Depression Inventory (BDI-II) Scores

Secondary: Change From Baseline in Beck Depression Inventory (BDI-II) Scores

Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

Secondary: Mean Numerical Rating Scale (NRS) Scores

Secondary: Mean Numerical Rating Scale (NRS) Scores

Secondary: Summary of Patient Global Impression of Change (PGIC) Scores

Secondary: Summary of Patient Global Impression of Change (PGIC) Scores

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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