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

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)

Population: 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).

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

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

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

Population: 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.

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

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

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

Population: 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.

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

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

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

Population: 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.

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

Population: MITT Population

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

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

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

Population: 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.

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

Population: 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.

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

Population: 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.

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