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Study No: VRX-RET-E22-108
Title : A Randomized, Double-Blind, Placebo- and Active-Controlled Crossover Study to Evaluate the Abuse Potential
of Retigabine in Recreational Polydrug Users
Rationale: This clinical abuse potential study was undertaken to rigorously examine the potential for clinical abuse
liability, as expected by the US Food & Drug Administration prior to marketing authorization for most novel central
nervous system (CNS) active compounds.
Phase: I
Study Period: 15 January 2008 - 28 May 2008
Study Design: This study was a double-blind, placebo- and active-controlled 7 period crossover study to evaluate the
abuse potential of single doses of retigabine compared with placebo, alprazolam, and levetiracetam. The study
consisted of a Screening visit, a Qualification Phase, a Treatment Phase (7 treatment periods), and a safety Follow-up
visit. The randomization schedule was established such that no subject would not receive the 900 mg dose of
retigabine prior to having received the 600 mg dose (i.e., the 600 mg and 900 mg/placebo treatment period could have
occurred at any time throughout the study, as long as the 600 mg treatment period occurred prior to the 900
mg/placebo treatment period). Based on an unexpected SAE experienced in one subject in the first cohort of 6
subjects who received retigabine 900mg, the protocol was amended and all subsequent subjects who were
randomised to retigabine 900mg received placebo instead.
Centers: One study center in Canada.
Indication: None
Treatment: Alprazolam (Xanax® or equivalent) 0.5mg overencapsulated tablets were utilized to administer 2mg
(Qualification) and 1.5mg and 3mg (Treatment) doses administered as single oral doses.
Levetiracetam (Keppra®) 500mg overencapsulated tablets were utilized to administer a 4000mg single oral dose.
Placebo was administered twice (once during Qualification and once during Treatment). Placebo retigabine was
identical in appearance to retigabine. Alprazolam placebo and levetiracetam placebo were similar in appearance to
alprazolam and levetiracetam (placebo and active were over-encapsulated with the same capsules).
The following treatments were used in the Qualification Phase:
• Treatment A: Alprazolam 2 mg (4 overencapsulated 0.5 mg alprazolam tablets)
• Treatment B: Placebo (4 overencapsulated placebo tablets)
The following treatments were used in the Treatment Phase:
• Treatment A: Placebo: 9 retigabine placebo tablets + 6 overencapsulated alprazolam placebo tablets + 8
overencapsulated levetiracetam placebo tablets
• Treatment B: Alprazolam 1.5 mg: 3 overencapsulated 0.5 mg alprazolam tablets + 3 overencapsulated
alprazolam placebo tablets + 8 overencapsulated levetiracetam placebo tablets + 9 retigabine placebo tablets
• Treatment C: Alprazolam 3 mg: 6 overencapsulated 0.5 mg alprazolam tablets + 9 retigabine placebo tablets + 8
overencapsulated levetiracetam placebo tablets
• Treatment D: Levetiracetam 4000 mg: 8 overencapsulated 500 mg levetiracetam tablets + 6 overencapsulated
alprazolam placebo tablets + 9 retigabine placebo tablets
• Treatment E: Retigabine 300 mg: 3 retigabine 100 mg tablets + 6 retigabine placebo tablets + 6 overencapsulated
alprazolam placebo tablets + 8 overencapsulated levetiracetam placebo tablets
• Treatment F: Retigabine 600 mg: 6 retigabine 100 mg tablets + 3 retigabine placebo tablet + 6 overencapsulated
alprazolam placebo tablets + 8 overencapsulated levetiracetam placebo tablets
• Treatment G: Retigabine 900 mg: 9 retigabine 100 mg tablets + 6 overencapsulated alprazolam placebo tablets +
8 overencapsulated levetiracetam placebo tablets or placebo (as described in Treatment A) if 600 mg retigabine
was not well tolerated
Objectives: The primary objectives of this study were to evaluate the abuse potential of retigabine compared to
placebo, to evaluate the abuse potential of retigabine compared to alprazolam, and to evaluate the abuse potential of
alprazolam compared to placebo (study validity).
The secondary objectives of this study were to evaluate the abuse potential of retigabine compared to levetiracetam, to
evaluate the abuse potential of levetiracetam compared to placebo, and to evaluate the safety and tolerability of
retigabine.
1
Criteria for Evaluation:
Pharmacodynamics (PD): The primary pharmacodynamic measures consisted of the visual analog scale (VAS) for
Drug Liking (“at this moment”), end-of-day and next-day Overall Drug Liking VAS and Take Drug Again VAS, and the
Addiction Research Centre Inventory (ARCI) Morphine Benzedrine Group (MBG) scale.
Secondary measures were included to evaluate other subjective effects including balance/positive effects (High VAS,
Subjective Drug Value [SDV], Good Drug Effects VAS, Pleasant Mental/Pleasant Physical State VASs), negative
effects (Bad Drug Effects VAS, ARCI Lysergic Acid Diethylamide [LSD]), sedative effects (ARCI Pentobarbital and
Chlorpromazine Group [PCAG]), perceptual/dissociative effects (Floating VAS, Colors Brighter VAS, Sounds Louder
VAS), and other drug effects (Any Drug Effects VAS, Alertness/Drowsiness VAS, Drug Similarity VASs, Dizziness
VAS, and ARCI Amphetamine and Benzedrine Group [BG] scales).
Objective measures were included to assess neurocognitive effects (Choice Reaction Time [CRT] Motor Reaction
Time [MRT], Recognition Reaction Time [RRT], Total Reaction Time [TRT], percentage correct responses and Divided
Attention [DA] test mean hit latency, mean greatest distance, mean percentage over road, Root Mean Square [RMS]
distance, percentage of target hits, and number of false alarms).
Pharmacokinetics (PK): Pharmacokinetic measures of retigabine were included to confirm exposure and, if
necessary, to aid in the interpretation of unusual responses. The following pharmacokinetic endpoints were evaluated:
plasma concentration-time data and the area under the plasma concentration versus time curve from time zero to the
time of the last measurable concentration [AUC(0-t)].
Safety: The safety measures for this study were vital signs, electrocardiograms (ECGs), physical examination, clinical
laboratory tests, and adverse events (AEs). Clinical laboratory tests, vital signs results, and ECG results are not
reported in this summary.
Statistical Methods:
Analysis Populations:
The Randomized Population was planned to include all subjects who were assigned a randomization number during
the Treatment Phase. Only randomized subjects were to be entered into the clinical database.
The Safety Population was planned to include all randomized subjects who received at least one dose of study drug
in the Treatment Phase.
The Per-Protocol Population was planned to include all randomized subjects who completed all 7 treatment periods
of the study and had no major protocol violations. The Per-Protocol Population was used for the pharmacokinetic
analyses.
The Pharmacodynamic Population was planned to include all randomized subjects who completed treatments A to F
and had no major protocol violations during treatment sessions. The analysis for the Pharmacodynamic Population
was to be the primary pharmacodynamic analysis for this study.
Pharmacodynamic Analysis: Primary endpoints (mean maximum score [Emax] and/or mean minimum score [Emin])
for the primary and secondary measures were analyzed using a mixed-effect model for a crossover study. Timeweighted mean (TWmean) values for all measures (primary and secondary) were calculated as secondary endpoints
and analyzed using a mixed-effect model. Primary and secondary endpoints were analyzed using a standard mixedeffect analysis of variance (ANOVA) or covariance (ANCOVA) model for crossover study. The model included
sequence, treatment, and period as fixed effects and subject as a random effect. From each model, means and 95%
confidence intervals (CIs) for treatments and treatment differences were provided. P-values were provided where
appropriate and multiplicity adjustment was undertaken for the primary endpoints using the Benjamini-Hochberg
procedure. Although multiplicity adjustments were performed on the primary endpoints, inferences and conclusions
were based primarily on un-adjusted p-values (p<0.05) for the primary and secondary endpoints, as well as a review of
the descriptive and graphical data.
The primary contrasts included:
•
Each dose of retigabine compared to placebo
•
Each dose of retigabine compared to each dose of alprazolam
•
Each dose of alprazolam compared to placebo (study validity)
The secondary contrasts included:
•
Each dose of retigabine compared to levetiracetam
•
Levetiracetam compared to placebo
Pharmacodynamic data at each time point were summarized by descriptive statistics and presented graphically (where
appropriate) for the Per-Protocol Population. All derived endpoints were summarized using descriptive statistics (n,
mean, standard deviation [SD], median, minimum, and maximum) for the Per-Protocol Population. Box-plots of the
derived parameters were presented for the Per-Protocol Population for selected endpoints (e.g., selected primary or
secondary measures).
2
In addition, descriptive statistics of Qualification Phase data (responders and non-responders) were provided. Placebo
data from any subjects not receiving the 900mg retigabine dose was summarized descriptively but not used in any
analyses.
Pharmacokinetic Analysis. Pharmacokinetic parameters for plasma retigabine were calculated as follows:
AUC(0-t): Area under the plasma concentration versus time curve from time zero to the time of the last measurable
concentration (t), as calculated by the linear trapezoidal method. While the AUC(0-t) was determined, it is recognized
that the limited sampling in this protocol precludes accurate estimation of this parameter..
Safety Analysis. Summary statistics were calculated for safety data.
Study Population: Healthy male and female subjects aged 18 to 55 (inclusive) who were recreational polydrug users
with a history of central nervous system (CNS) depressant use, and who met qualification criteria.
Number of Subjects:
Total (%)
Planned N
35
Qualification Phase1 (subjects received either alprazolam 2 mg or placebo)
81
Randomized Population
36 (100.0)
Safety Population
36 (100.0)
Per-Protocol Population
26 (72.2)
Pharmacodynamic Population
26 (72.2)
Took RTG 900mg
6 (16.7)
Took retigabine 900mg and included in Pharmacodynamic Population
3 (8.3)
Completed n (%)
26 (72.2)
Total Number Subjects Withdrawn N (%)
10 (27.8)
Withdrawn due to Adverse Events n (%)
3 (8.3)
Withdrawn for Other Reasons n (%)
7 (25%)
1. Of the 81 subjects in the qualification phase, 45 were considered eligible for the Treatment Phase, 32 subjects
failed the qualifying criteria, and 4 did not complete qualification.
Demographics
Randomized and Safety Population
Pharmacodynamic and Per Protocol
Populations
N (Safety Population)
36
26
Females: Males
7: 29
5: 21
Mean Age in Years (SD)
36.7 (9.11)
37.4 (9.89)
Mean Weight in Kg (SD)
74.64 (11.740)
72.90 (11.488)
White n (%)
30 (83.3)
21 (80.8)
3
Pharmacodynamics (PD): Emax and/or Emin were the primary endpoints for the PD parameters. TWmean was a
supportive PD parameter. Emax was used for the trial validity endpoint and those values are presented in the tables
below.
PD parameters are summarized in the tables below under the following categories:
• Balance of Drug Effects Variables
• Positive Drug Effects Variables
• Negative Drug Effects Variable
• Sedative Drug Effects Variable
• Dissociative Drug Effects Variables
• Other Drug Effects Variables
• Objective Measures
Pharmacodynamics Primary Endpoints:
Trial Validity: The 95% CIs of differences in Emax for the primary measures (VAS Drug Liking [at this moment], VAS
Overall Drug Liking, VAS Take Drug Again, and ARCI MBG) between both doses of alprazolam and placebo did not
include zero; therefore, the criteria for trial validity were met.
Balance of Effects Variables:
Analysis of Variance: Drug Liking VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Adjusted P-value
Retigabine 300mg − Placebo
17.0 (7.0, 27.1)
0.001
0.002
Retigabine 600mg − Placebo
22.9 (14.0, 31.9)
<0.001
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-3.4 (-12.8, 6.0)
0.473
0.632
Retigabine 600mg − Alprazolam 1.5mg
2.5 (-6.2, 11.1)
0.574
0.632
Retigabine 300mg − Alprazolam 3mg
-8.2 (-16.6, 0.2)
0.055
0.101
Retigabine 600mg − Alprazolam 3mg
-2.3 (-10.4, 5.8)
0.569
0.632
Alprazolam 1.5mg − Placebo
20.5 (12.3, 28.6)
<0.001
<0.001
Alprazolam 3mg − Placebo
25.3 (16.5, 34.0)
<0.001
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-4.0 (-12.1, 4.2)
0.338
0.531
Retigabine 600mg − Levetiracetam 4000mg
1.9 (-6.3, 10.2)
0.644
0.644
Levetiracetam 4000mg − Placebo
21.0 (11.2, 30.8)
<0.001
<0.001
Drug Liking VAS item: “At this moment, my liking for this drug is”, where 0 = Strong disliking, 100 = Strong liking, and
50 = Neutral
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period and treatment as fixed effects, and subject within treatment sequence as a random effect.
Analysis of Variance: Overall Drug Liking VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Adjusted P-value
Retigabine 300mg − Placebo
9.9 (-2.3, 22.1)
0.112
0.206
Retigabine 600mg − Placebo
17.5 (6.5, 28.4)
0.002
0.011
Retigabine 300mg − Alprazolam 1.5mg
-4.5 (-16.0, 6.9)
0.436
0.599
Retigabine 600mg − Alprazolam 1.5mg
3.0 (-7.6, 13.6)
0.572
0.684
Retigabine 300mg − Alprazolam 3mg
-8.9 (-19.2, 1.3)
0.087
0.192
Retigabine 600mg − Alprazolam 3mg
-1.4 (-11.3, 8.5)
0.784
0.784
Alprazolam 1.5mg − Placebo
14.4 (4.4, 24.4)
0.005
0.019
Alprazolam 3mg − Placebo
18.8 (8.1, 29.5)
<0.001
0.008
Retigabine 300mg − Levetiracetam 4000mg
-2.5 (-12.4, 7.4)
0.622
0.684
Retigabine 600mg − Levetiracetam 4000mg
5.1 (-5.0, 15.1)
0.319
0.502
Levetiracetam 4000mg − Placebo
12.4 (0.4, 24.3)
0.043
0.117
Overall Drug Liking VAS item: “Overall, my liking for this drug is”, where 0 = Strong disliking, 100 = Strong liking, and
50 = Neutral
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period and treatment as fixed effects, and subject within treatment sequence as a random effect.
4
Analysis of Variance: Take Drug Again VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Adjusted P-value
Retigabine 300mg − Placebo
21.1 (3.0, 39.3)
0.023
0.050
Retigabine 600mg − Placebo
33.2 (16.9, 49.4)
<0.001
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-9.2 (-26.2, 7.8)
0.288
0.453
Retigabine 600mg − Alprazolam 1.5mg
2.9 (-12.8, 18.6)
0.718
0.790
Retigabine 300mg − Alprazolam 3mg
-10.9 (-26.1, 4.3)
0.159
0.291
Retigabine 600mg − Alprazolam 3mg
1.1 (-13.6, 15.8)
0.881
0.881
Alprazolam 1.5mg − Placebo
30.3 (15.5, 45.1)
<0.001
<0.001
Alprazolam 3mg − Placebo
32.0 (16.2, 47.9)
<0.001
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-4.8 (-19.5, 10.0)
0.524
0.640
Retigabine 600mg − Levetiracetam 4000mg
7.3 (-7.6, 22.2)
0.336
0.462
Levetiracetam 4000mg − Placebo
25.9 (8.2, 43.6)
0.005
0.013
Take Drug Again VAS item: “I would take this drug again,” where 0 = Definitely not and 100 = Definitely so
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period and treatment as fixed effects, and subject within treatment sequence as a random effect.
Analysis of Covariance: ARCI MBG Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Adjusted P-value
Retigabine 300mg − Placebo
3.5 (1.2, 5.8)
0.004
0.008
Retigabine 600mg − Placebo
4.8 (2.7, 6.9)
<0.001
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-1.0 (-3.2, 1.2)
0.352
0.484
Retigabine 600mg − Alprazolam 1.5mg
0.3 (-1.7, 2.3)
0.790
0.869
Retigabine 300mg − Alprazolam 3mg
-1.8 (-3.8, 0.1)
0.069
0.126
Retigabine 600mg − Alprazolam 3mg
-0.5 (-2.4, 1.4)
0.582
0.712
Alprazolam 1.5mg − Placebo
4.5 (2.6, 6.4)
<0.001
<0.001
Alprazolam 3mg − Placebo
5.3 (3.3, 7.4)
<0.001
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-0.1 (-2.0, 1.8)
0.937
0.937
Retigabine 600mg − Levetiracetam 4000mg
1.2 (-0.7, 3.2)
0.206
0.324
Levetiracetam 4000mg − Placebo
3.6 (1.3, 5.9)
0.002
0.006
ARCI MBG values can range from 0 = No euphoria to 16 = Strong euphoria
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Pharmacodynamics (PD) Secondary Endpoints:
Balance of Drug Effects Variables:
Analysis of Covariance: Pleasant Mental State VAS Emin – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-4.3 (-15.3, 6.7)
0.441
Retigabine 600mg − Placebo
-5.3 (-15.1, 4.5)
0.288
Retigabine 300mg − Alprazolam 1.5mg
8.8 (-1.5, 19.0)
0.092
Retigabine 600mg − Alprazolam 1.5mg
7.8 (-1.7, 17.2)
0.106
Retigabine 300mg − Alprazolam 3mg
10.1 (0.9, 19.3)
0.031
Retigabine 600mg − Alprazolam 3mg
9.1 (0.3, 18.0)
0.044
Alprazolam 1.5mg − Placebo
-13.1 (-22.1, -4.1)
0.005
Alprazolam 3mg − Placebo
-14.4 (-24.0, -4.8)
0.004
Retigabine 300mg − Levetiracetam 4000mg
6.9 (-1.9, 15.8)
0.124
Retigabine 600mg − Levetiracetam 4000mg
5.9 (-3.0, 14.9)
0.193
Levetiracetam 4000mg − Placebo
-11.2 (-22.0, -0.5)
0.040
Pleasant Mental State VAS item: “The feeling in my mind is”, where 0 = Very unpleasant, 100 = Very pleasant, and 50
= Neutral
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
5
Analysis of Covariance: Pleasant Physical State VAS Emin – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-8.5 (-19.4, 2.4)
0.126
Retigabine 600mg − Placebo
-9.8 (-19.5, -0.1)
0.049
Retigabine 300mg − Alprazolam 1.5mg
5.6 (-4.6, 15.8)
0.281
Retigabine 600mg − Alprazolam 1.5mg
4.3 (-5.1, 13.7)
0.371
Retigabine 300mg − Alprazolam 3mg
11.3 (2.2, 20.4)
0.016
Retigabine 600mg − Alprazolam 3mg
10.0 (1.2, 18.8)
0.026
Alprazolam 1.5mg − Placebo
-14.1 (-23.0, -5.2)
0.002
Alprazolam 3mg − Placebo
-19.8 (-29.3, -10.3)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
4.2 (-4.6, 13.1)
0.344
Retigabine 600mg − Levetiracetam 4000mg
2.9 (-6.0, 11.9)
0.519
Levetiracetam 4000mg − Placebo
-12.7 (-23.4, -2.1)
0.020
Pleasant Physical State VAS item: “The feeling in my body is”, where 0 = Very unpleasant, 100 = Very pleasant, and
50 = Neutral
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Positive Drug Effects Variables:
Analysis of Variance: Subjective Drug Value Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
9.27 (0.82, 17.72)
0.032
Retigabine 600mg − Placebo
10.08 (2.53, 17.62)
0.009
Retigabine 300mg − Alprazolam 1.5mg
-2.86 (-10.77, 5.06)
0.476
Retigabine 600mg − Alprazolam 1.5mg
-2.05 (-9.36, 5.26)
0.579
Retigabine 300mg − Alprazolam 3mg
-6.18 (-13.27, 0.91)
0.087
Retigabine 600mg − Alprazolam 3mg
-5.38 (-12.20, 1.45)
0.122
Alprazolam 1.5mg − Placebo
12.13 (5.23, 19.03)
<0.001
Alprazolam 3mg − Placebo
15.45 (8.06, 22.85)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
1.33 (-5.53, 8.18)
0.702
Retigabine 600mg − Levetiracetam 4000mg
2.13 (-4.81, 9.07)
0.545
Levetiracetam 4000mg − Placebo
7.95 (-0.30, 16.20)
0.059
SDV values can range from $0.25 (low value) to $50.00 (high value)
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period and treatment as fixed effects, and subject within treatment sequence as a random effect.
Analysis of Variance: Good Drug Effects VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
39.0 (24.3, 53.7)
<0.001
Retigabine 600mg − Placebo
50.4 (37.3, 63.5)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-5.1 (-18.9, 8.6)
0.463
Retigabine 600mg − Alprazolam 1.5mg
6.3 (-6.4, 19.0)
0.331
Retigabine 300mg − Alprazolam 3mg
-11.8 (-24.2, 0.5)
0.059
Retigabine 600mg − Alprazolam 3mg
-0.5 (-12.3, 11.4)
0.938
Alprazolam 1.5mg − Placebo
44.1 (32.1, 56.1)
<0.001
Alprazolam 3mg − Placebo
50.9 (38.0, 63.7)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-5.9 (-17.8, 6.0)
0.327
Retigabine 600mg − Levetiracetam 4000mg
5.5 (-6.6, 17.5)
0.373
Levetiracetam 4000mg − Placebo
44.9 (30.6, 59.3)
<0.001
Good Drug Effects VAS item: “I can feel good drug effects”, where 0 = Definitely not and 100 = Definitely so
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period, and treatment as fixed effects, and subject within treatment sequence as a random effect.
6
Analysis of Covariance: High VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
45.6 (30.1, 61.1)
<0.001
Retigabine 600mg − Placebo
60.8 (47.0, 74.7)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-10.2 (-24.9, 4.4)
0.170
Retigabine 600mg − Alprazolam 1.5mg
5.0 (-8.4, 18.4)
0.463
Retigabine 300mg − Alprazolam 3mg
-21.2 (-34.2, -8.1)
0.002
Retigabine 600mg − Alprazolam 3mg
-6.0 (-18.5, 6.6)
0.349
Alprazolam 1.5mg − Placebo
55.8 (43.1, 68.6)
<0.001
Alprazolam 3mg − Placebo
66.8 (53.2, 80.4)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-10.5 (-23.1, 2.2)
0.104
Retigabine 600mg − Levetiracetam 4000mg
4.7 (-8.0, 17.5)
0.463
Levetiracetam 4000mg − Placebo
56.1 (40.9, 71.3)
<0.001
High VAS item: “I am feeling high”, where 0 = Definitely not and 100 = Definitely so
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Negative Drug Effects Variables:
Analysis of Variance: Bad Drug Effects VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
17.4 (-0.1, 35.0)
0.051
Retigabine 600mg − Placebo
31.0 (15.4, 46.7)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-3.9 (-20.4, 12.5)
0.636
Retigabine 600mg − Alprazolam 1.5mg
9.6 (-5.5, 24.8)
0.211
Retigabine 300mg − Alprazolam 3mg
-28.6 (-43.3, -13.8)
<0.001
Retigabine 600mg − Alprazolam 3mg
-15.0 (-29.2, -0.8)
0.038
Alprazolam 1.5mg − Placebo
21.4 (7.1, 35.7)
0.004
Alprazolam 3mg − Placebo
46.0 (30.7, 61.4)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-6.6 (-20.9, 7.6)
0.357
Retigabine 600mg − Levetiracetam 4000mg
6.9 (-7.5, 21.3)
0.343
Levetiracetam 4000mg − Placebo
24.1 (7.0, 41.2)
0.006
Bad Drug Effects VAS item: “I can feel bad drug effects”, where 0 = Definitely not and 100 = Definitely so
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period and treatment as fixed effects, and subject within treatment sequence as a random effect.
Analysis of Covariance: ARCI LSD Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
1.5 (0.1, 2.9)
0.032
Retigabine 600mg − Placebo
2.8 (1.5, 4.0)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-0.7 (-2.0, 0.5)
0.255
Retigabine 600mg − Alprazolam 1.5mg
0.5 (-0.7, 1.7)
0.396
Retigabine 300mg − Alprazolam 3mg
-1.4 (-2.6, -0.3)
0.015
Retigabine 600mg − Alprazolam 3mg
-0.2 (-1.3, 0.9)
0.746
Alprazolam 1.5mg − Placebo
2.3 (1.1, 3.4)
<0.001
Alprazolam 3mg − Placebo
3.0 (1.8, 4.2)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
0.2 (-0.9, 1.3)
0.729
Retigabine 600mg − Levetiracetam 4000mg
1.5 (0.3, 2.6)
0.012
Levetiracetam 4000mg − Placebo
1.3 (-0.0, 2.7)
0.055
ARCI LSD values can range from 0 = No dysphoria to 14 = Strong dysphoria
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
7
Sedative Drug Effects Variables:
Analysis of Covariance: Drowsiness VAS Emin – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-14.5 (-25.1, -4.0)
0.007
Retigabine 600mg − Placebo
-19.4 (-28.9, -10.0)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
19.2 (9.4, 29.1)
<0.001
Retigabine 600mg − Alprazolam 1.5mg
14.3 (5.2, 23.4)
0.002
Retigabine 300mg − Alprazolam 3mg
25.9 (17.1, 34.7)
<0.001
Retigabine 600mg − Alprazolam 3mg
21.0 (12.5, 29.5)
<0.001
Alprazolam 1.5mg − Placebo
-33.7 (-42.3, -25.1)
<0.001
Alprazolam 3mg − Placebo
-40.4 (-49.6, -31.2)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
7.2 (-1.3, 15.7)
0.096
Retigabine 600mg − Levetiracetam 4000mg
2.3 (-6.3, 10.9)
0.601
Levetiracetam 4000mg − Placebo
-21.7 (-32.0, -11.4)
<0.001
Drowsiness VAS item: “My mental state is”, where 0= Very drowsy and 100 = Very alert
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: ARCI PCAG Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
4.8 (3.1, 6.5)
<0.001
Retigabine 600mg − Placebo
4.8 (3.3, 6.3)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-2.2 (-3.8, -0.7)
0.005
Retigabine 600mg − Alprazolam 1.5mg
-2.2 (-3.6, -0.8)
0.003
Retigabine 300mg − Alprazolam 3mg
-4.1 (-5.5, -2.7)
<0.001
Retigabine 600mg − Alprazolam 3mg
-4.1 (-5.4, -2.8)
<0.001
Alprazolam 1.5mg − Placebo
7.0 (5.7, 8.4)
<0.001
Alprazolam 3mg − Placebo
8.9 (7.5, 10.4)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-1.2 (-2.5, 0.2)
0.090
Retigabine 600mg − Levetiracetam 4000mg
-1.1 (-2.5, 0.2)
0.103
Levetiracetam 4000mg − Placebo
6.0 (4.3, 7.6)
<0.001
ARCI PCAG values range from 0 = No sedation to 15 = Strong sedation
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Dissociative Drug Effects Variables:
Analysis of Covariance: Floating VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
32.2 (16.5, 47.8)
<0.001
Retigabine 600mg − Placebo
40.1 (26.1, 54.1)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-13.6 (-28.3, 1.1)
0.070
Retigabine 600mg − Alprazolam 1.5mg
-5.7 (-19.2, 7.9)
0.410
Retigabine 300mg − Alprazolam 3mg
-25.8 (-39.0, -12.7)
<0.001
Retigabine 600mg − Alprazolam 3mg
-17.9 (-30.6, -5.3)
0.006
Alprazolam 1.5mg − Placebo
45.8 (33.0, 58.5)
<0.001
Alprazolam 3mg − Placebo
58.0 (44.3, 71.7)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-4.8 (-17.5, 7.9)
0.455
Retigabine 600mg − Levetiracetam 4000mg
3.1 (-9.7, 16.0)
0.633
Levetiracetam 4000mg − Placebo
37.0 (21.7, 52.3)
<0.001
Floating VAS item: “I feel as if I am floating”, where 0 = Not at all and 100 = Very much
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
8
Analysis of Variance: Colors Brighter VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
3.4 ( -2.5, 9.3)
0.252
Retigabine 600mg − Placebo
6.6 ( 1.3, 11.9)
0.014
Retigabine 300mg − Alprazolam 1.5mg
1.4 ( -4.1, 6.9)
0.611
Retigabine 600mg − Alprazolam 1.5mg
4.6 ( -0.5, 9.7)
0.077
Retigabine 300mg − Alprazolam 3mg
-2.2 ( -7.2, 2.8)
0.386
Retigabine 600mg − Alprazolam 3mg
1.0 ( -3.9, 5.8)
0.686
Alprazolam 1.5mg − Placebo
2.0 ( -2.8, 6.8)
0.411
Alprazolam 3mg − Placebo
5.6 ( 0.4, 10.8)
0.036
Retigabine 300mg − Levetiracetam 4000mg
1.8 ( -2.9, 6.6)
0.446
Retigabine 600mg − Levetiracetam 4000mg
5.0 ( 0.2, 9.9)
0.043
Levetiracetam 4000mg − Placebo
1.6 ( -4.2, 7.4)
0.590
Note: Least squares means were estimated from a linear mixed-effect ANCOVA with treatment sequence, period and
treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence as a
random effect.
Analysis of Variance: Sounds Louder VAS Emax – Pharmacodynamic Population
Retigabine 300mg − Placebo
4.8 ( -0.6, 10.1)
0.079
Retigabine 600mg − Placebo
6.2 ( 1.4, 10.9)
0.012
Retigabine 300mg − Alprazolam 1.5mg
2.5 ( -2.5, 7.5)
0.319
Retigabine 600mg − Alprazolam 1.5mg
3.9 ( -0.7, 8.5)
0.097
Retigabine 300mg − Alprazolam 3mg
-4.2 ( -8.7, 0.2)
0.063
Retigabine 600mg − Alprazolam 3mg
-2.9 ( -7.2, 1.5)
0.197
Alprazolam 1.5mg − Placebo
2.3 ( -2.1, 6.6)
0.309
Alprazolam 3mg − Placebo
9.0 ( 4.3, 13.7)
<.001
Retigabine 300mg − Levetiracetam 4000mg
0.9 ( -3.4, 5.2)
0.678
Retigabine 600mg − Levetiracetam 4000mg
2.3 ( -2.1, 6.7)
0.303
Levetiracetam 4000mg − Placebo
3.9 ( -1.3, 9.1)
0.144
Note: Least squares means were estimated from a linear mixed-effect ANCOVA with treatment sequence, period and
treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence as a
random effect.
Other Drug Effects Variables:
Analysis of Variance: Any Drug Effects VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
47.1 (31.8, 62.3)
<0.001
Retigabine 600mg − Placebo
53.1 (39.5, 66.8)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-8.7 (-23.0, 5.5)
0.228
Retigabine 600mg − Alprazolam 1.5mg
-2.7 (-15.9, 10.5)
0.690
Retigabine 300mg − Alprazolam 3mg
-18.1 (-30.9, -5.4)
0.006
Retigabine 600mg − Alprazolam 3mg
-12.1 (-24.4, 0.3)
0.055
Alprazolam 1.5mg − Placebo
55.8 (43.3, 68.3)
<0.001
Alprazolam 3mg − Placebo
65.2 (51.9, 78.6)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-6.3 (-18.6, 6.1)
0.318
Retigabine 600mg − Levetiracetam 4000mg
-0.2 (-12.7, 12.4)
0.977
Levetiracetam 4000mg − Placebo
53.3 (38.4, 68.2)
<0.001
Any Drug Effects VAS item: “I can feel any drug effects”, where 0 = Definitely not and 100 = Definitely so
Note: Least squares means were estimated from a linear mixed-effect analysis of variance with treatment sequence,
period and treatment as fixed effects, and subject within treatment sequence as a random effect.
9
Analysis of Covariance: Dizziness VAS Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
31.0 (14.9, 47.2)
<0.001
Retigabine 600mg − Placebo
37.9 (23.5, 52.3)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-13.5 (-28.8, 1.7)
0.081
Retigabine 600mg − Alprazolam 1.5mg
-6.7 (-20.7, 7.3)
0.347
Retigabine 300mg − Alprazolam 3mg
-34.6 (-48.3, -21.0)
<0.001
Retigabine 600mg − Alprazolam 3mg
-27.8 (-40.8, -14.7)
<0.001
Alprazolam 1.5mg − Placebo
44.6 (31.4, 57.8)
<0.001
Alprazolam 3mg − Placebo
65.7 (51.6, 79.8)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-17.2 (-30.3, -4.1)
0.010
Retigabine 600mg − Levetiracetam 4000mg
-10.3 (-23.6, 2.9)
0.124
Levetiracetam 4000mg − Placebo
48.3 (32.6, 64.0)
<0.001
Dizziness VAS item: “I am feeling dizzy”, where 0 = Definitely not and 100 = Definitely so
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: ARCI Amphetamine Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
1.9 (0.5, 3.3)
0.007
Retigabine 600mg − Placebo
2.3 (1.1, 3.5)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
-0.5 (-1.8, 0.8)
0.463
Retigabine 600mg − Alprazolam 1.5mg
-0.1 (-1.3, 1.1)
0.896
Retigabine 300mg − Alprazolam 3mg
-1.0 (-2.1, 0.2)
0.102
Retigabine 600mg − Alprazolam 3mg
-0.6 (-1.7, 0.6)
0.320
Alprazolam 1.5mg − Placebo
2.4 (1.3, 3.5)
<0.001
Alprazolam 3mg − Placebo
2.9 (1.7, 4.1)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
0.2 (-1.0, 1.3)
0.780
Retigabine 600mg − Levetiracetam 4000mg
0.6 (-0.6, 1.7)
0.330
Levetiracetam 4000mg − Placebo
1.8 (0.4, 3.1)
0.011
ARCI Amphetamine values range from 0 = No stimulation/euphoria to 11= Strong stimulation/euphoria
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: ARCI BG Emin – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-2.0 (-3.0, -0.9)
<0.001
Retigabine 600mg − Placebo
-2.1 (-3.0, -1.2)
<0.001
Retigabine 300mg − Alprazolam 1.5mg
1.2 (0.2, 2.2)
0.015
Retigabine 600mg − Alprazolam 1.5mg
1.1 (0.2, 2.0)
0.019
Retigabine 300mg − Alprazolam 3mg
1.6 (0.7, 2.4)
<0.001
Retigabine 600mg − Alprazolam 3mg
1.4 (0.6, 2.3)
0.001
Alprazolam 1.5mg − Placebo
-3.2 (-4.1, -2.3)
<0.001
Alprazolam 3mg − Placebo
-3.5 (-4.5, -2.6)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
0.2 (-0.6, 1.1)
0.565
Retigabine 600mg − Levetiracetam 4000mg
0.1 (-0.7, 1.0)
0.788
Levetiracetam 4000mg − Placebo
-2.2 (-3.3, -1.2)
<0.001
ARCI BG values range from 0 = Less/no mental stimulation to 13= More/strong mental stimulation
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period and treatment as fixed effects, baseline (pre-dose) value as a covariate, and subject within treatment sequence
as a random effect.
10
Descriptive Statistics: Drug Similarity VASs at 12 hours Postdose – Pharmacodynamic Population
Drug
Placebo
Alprazolam
Alprazolam
Levetiracetam
Retigabine
Retigabine
Similarity
1.5mg
3mg
4000mg
300mg
600mg
VAS (N)1
Overall familiarity (N=26)
Mean (SD)
44.4 (32.08)
61.2 (27.48)
56.6 (33.44)
56.5 (25.83)
47.0 (25.80)
53.1 (24.33)
Median
50.0 (0-100)
66.5 (0-100)
64.5 (0-100)
58.0 (1-100)
50.5 (0-94)
57.0 (0-93)
(Range)
Placebo (N=26)
Mean (SD)
61.4 (41.06)
13.4 (26.41)
3.3 (8.96)
7.6 (17.10)
28.1 (38.56) 14.7 (25.69)
Median
73.0 (0-100)
0.0 (0-100)
0.0 (0-44)
0.0 (0-53)
0.0 (0-100)
0.0 (0-74)
(Range)
Benzodiazepines (N=12–14)
Mean (SD)
21.3 (23.99)
73.9 (27.61)
67.9 (33.43)
46.7 (27.95)
26.4 (34.97) 43.1 (35.27)
Median
12.5 (0-58)
77.0 (0-100)
74.5 (0-100)
54.5 (0-100)
5.5 (0-99)
53.5 (0-99)
(Range)
Codeine or morphine (N=13–15)
Mean (SD)
10.5 (17.63)
42.5 (30.63)
43.3 (38.90)
41.7 (28.28)
29.5 (28.14) 32.5 (33.62)
Median
2.0 (0-51)
52.0 (0-83)
57.0 (0-91)
50.0 (0-78)
36.0 (0-71)
11.0 (0-78)
(Range)
Ecstasy (MDMA) (N=20–22)
Mean (SD)
6.2 (17.42)
8.3 (17.36)
8.0 (17.28)
23.7 (25.61)
23.8 (32.51) 38.2 (32.09)
Median
0.0 (0-65)
0.0 (0-62)
0.5 (0-60)
10.5 (0-72)
3.5 (0-100)
46.0 (0-100)
(Range)
Cannabinoids (THC) (N=24–26)
Mean (SD)
7.2 (18.33)
27.8 (33.69)
42.9 (35.91)
33.6 (32.51)
25.2 (33.26) 31.9 (32.90)
Median
0.0 (0-64)
7.5 (0-93)
57.0 (0-100)
33.0 (0-98)
1.0 (0-94)
13.0 (0-94)
(Range)
1. N is the number of subjects who completed each VAS, based on the number of subjects who reported experience
with the drug/drug class at Screening.
MDMA = 3,4 methylenedioxymethamphetamine; THC = 9-Delta-tetrahydrocannabinol
Objective Measures:
Analysis of Covariance: CRT Motor Reaction Time (MRT) (msec) Emax - Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-14.1 ( -54.8, 26.5)
0.492
Retigabine 600mg − Placebo
15.7 ( -20.5, 51.9)
0.391
Retigabine 300mg − Alprazolam 1.5mg
-167.7 ( -205.7, -129.7)
<.001
Retigabine 600mg − Alprazolam 1.5mg
-137.8 ( -173.0, -102.6)
<.001
Retigabine 300mg − Alprazolam 3mg
-227.8 ( -262.6, -193.1)
<.001
Retigabine 600mg − Alprazolam 3mg
-198.0 ( -231.7, -164.2)
<.001
Alprazolam 1.5mg − Placebo
153.5 ( 120.3, 186.8)
<.001
Alprazolam 3mg − Placebo
213.7 ( 177.3, 250.0)
<.001
Retigabine 300mg − Levetiracetam 4000mg
-32.4 ( -65.5, 0.7)
0.055
Retigabine 600mg − Levetiracetam 4000mg
-2.5 ( -36.3, 31.2)
0.882
Levetiracetam 4000mg − Placebo
18.2 ( -21.8, 58.3)
0.369
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
11
Analysis of Covariance: CRT Recognition Reaction Time (RRT) (msec) Emax - Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
5.5 ( -22.4, 33.5)
0.696
Retigabine 600mg − Placebo
14.3 ( -10.5, 39.2)
0.256
Retigabine 300mg − Alprazolam 1.5mg
-44.5 ( -70.6, -18.3)
0.001
Retigabine 600mg − Alprazolam 1.5mg
-35.7 ( -59.9, -11.4)
0.004
Retigabine 300mg − Alprazolam 3mg
-79.9 ( -103.8, -56.1)
<.001
Retigabine 600mg − Alprazolam 3mg
-71.1 ( -94.3, -47.9)
<.001
Alprazolam 1.5mg − Placebo
50.0 ( 27.1, 72.9)
<.001
Alprazolam 3mg − Placebo
85.5 ( 60.5, 110.4)
<.001
Retigabine 300mg − Levetiracetam 4000mg
-9.1 ( -31.9, 13.7)
0.432
Retigabine 600mg − Levetiracetam 4000mg
-0.3 ( -23.6, 23.0)
0.982
Levetiracetam 4000mg − Placebo
14.6 ( -13.0, 42.2)
0.297
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: CRT Total Reaction Time (TRT) (msec) Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-12.8 (-76.0, 50.4)
0.690
Retigabine 600mg − Placebo
27.7 (-28.6, 84.0)
0.332
Retigabine 300mg − Alprazolam 1.5mg
-210.3 (-269.5, -151.2)
<0.001
Retigabine 600mg − Alprazolam 1.5mg
-169.9 (-224.7, -115.1)
<0.001
Retigabine 300mg − Alprazolam 3mg
-302.3 (-356.3, -248.2)
<0.001
Retigabine 600mg − Alprazolam 3mg
-261.8 (-314.3, -209.3)
<0.001
Alprazolam 1.5mg − Placebo
197.6 (145.8, 249.4)
<0.001
Alprazolam 3mg − Placebo
289.5 (233.0, 346.0)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-44.4 (-96.0, 7.1)
0.091
Retigabine 600mg − Levetiracetam 4000mg
-4.0 (-56.6, 48.7)
0.882
Levetiracetam 4000mg − Placebo
31.7 (-30.8, 94.1)
0.317
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: CRT Percentage Correct Responses (%) Emin – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-3.48 (-7.02, 0.06)
0.054
Retigabine 600mg − Placebo
-1.52 (-4.67, 1.64)
0.343
Retigabine 300mg − Alprazolam 1.5mg
11.66 (8.35, 14.97)
<0.001
Retigabine 600mg − Alprazolam 1.5mg
13.62 (10.57, 16.67)
<0.001
Retigabine 300mg − Alprazolam 3mg
18.19 (15.17, 21.21)
<0.001
Retigabine 600mg − Alprazolam 3mg
20.16 (17.23, 23.08)
<0.001
Alprazolam 1.5mg − Placebo
-15.14 (-18.02, -12.25)
<0.001
Alprazolam 3mg − Placebo
-21.67 (-24.83, -18.51)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-0.42 (-3.28, 2.44)
0.771
Retigabine 600mg − Levetiracetam 4000mg
1.54 (-1.35, 4.44)
0.294
Levetiracetam 4000mg − Placebo
-3.06 (-6.51, 0.40)
0.082
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
12
Analysis of Covariance: DA Mean RMS Distance (pixels) Emax – Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-0.37 (-11.08, 10.34)
0.946
Retigabine 600mg − Placebo
1.73 (-7.82, 11.28)
0.720
Retigabine 300mg − Alprazolam 1.5mg
-43.01 (-53.04, -32.99)
<0.001
Retigabine 600mg − Alprazolam 1.5mg
-40.91 (-50.16, -31.67)
<0.001
Retigabine 300mg − Alprazolam 3mg
-48.53 (-57.68, -39.38)
<0.001
Retigabine 600mg − Alprazolam 3mg
-46.43 (-55.30, -37.56)
<0.001
Alprazolam 1.5mg − Placebo
42.64 (33.92, 51.37)
<0.001
Alprazolam 3mg − Placebo
48.16 (38.62, 57.69)
<0.001
Retigabine 300mg − Levetiracetam 4000mg
-17.42 (-26.09, -8.76)
<0.001
Retigabine 600mg − Levetiracetam 4000mg
-15.32 (-24.10, -6.54)
<0.001
Levetiracetam 4000mg − Placebo
17.05 (6.60, 27.51)
0.002
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: Divided Attention (DA) Test : Mean Hit Latency (msec) – Emax – Pharmacodynamic
Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
5.0 ( -25.6, 35.6)
0.747
Retigabine 600mg − Placebo
1.6 ( -25.7, 28.8)
0.909
Retigabine 300mg − Alprazolam 1.5mg
-126.3 ( -154.9, -97.7)
<.001
Retigabine 600mg − Alprazolam 1.5mg
-129.7 ( -156.1, -103.3)
<.001
Retigabine 300mg − Alprazolam 3mg
-170.2 ( -196.4, -144.1)
<.001
Retigabine 600mg − Alprazolam 3mg
-173.6 ( -199.0, -148.3)
<.001
Alprazolam 1.5mg − Placebo
131.3 ( 106.3, 156.3)
<.001
Alprazolam 3mg − Placebo
175.2 ( 148.0, 202.5)
<.001
Retigabine 300mg − Levetiracetam 4000mg
-49.0 ( -73.7, -24.2)
<.001
Retigabine 600mg − Levetiracetam 4000mg
-52.4 ( -77.4, -27.3)
<.001
Levetiracetam 4000mg − Placebo
54.0 ( 24.1, 83.8)
<.001
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: Divided Attention (DA) Test : Mean Greatest Distance (pixels) – Emax –
Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-1.58 ( -26.76, 23.61)
0.901
Retigabine 600mg − Placebo
4.24 ( -18.19, 26.67)
0.709
Retigabine 300mg − Alprazolam 1.5mg
-93.23 ( -116.80, -69.65)
<.001
Retigabine 600mg − Alprazolam 1.5mg
-87.41 ( -109.12, -65.69)
<.001
Retigabine 300mg − Alprazolam 3mg
-111.08 ( -132.59, -89.56)
<.001
Retigabine 600mg − Alprazolam 3mg
-105.26 ( -126.12, -84.40)
<.001
Alprazolam 1.5mg − Placebo
91.65 ( 71.16, 112.14)
<.001
Alprazolam 3mg − Placebo
109.50 ( 87.04, 131.96)
<.001
Retigabine 300mg − Levetiracetam 4000mg
-37.83 ( -58.18, -17.49)
<.001
Retigabine 600mg − Levetiracetam 4000mg
-32.01 ( -52.64, -11.39)
0.003
Levetiracetam 4000mg − Placebo
36.25 ( 11.69, 60.82)
0.004
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
13
Analysis of Covariance: Divided Attention (DA) Test : Mean Percentage Over Road (%) – Emax –
Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
-1.16 ( -3.73, 1.41)
0.374
Retigabine 600mg − Placebo
-0.07 ( -2.35, 2.22)
0.953
Retigabine 300mg − Alprazolam 1.5mg
1.59 ( -0.81, 3.99)
0.191
Retigabine 600mg − Alprazolam 1.5mg
2.68 ( 0.47, 4.90)
0.018
Retigabine 300mg − Alprazolam 3mg
2.91 ( 0.71, 5.10)
0.010
Retigabine 600mg − Alprazolam 3mg
4.00 ( 1.87, 6.14)
<.001
Alprazolam 1.5mg − Placebo
-2.75 ( -4.85, -0.66)
0.010
Alprazolam 3mg − Placebo
-4.07 ( -6.37, -1.77)
<.001
Retigabine 300mg − Levetiracetam 4000mg
3.09 ( 1.01, 5.17)
0.004
Retigabine 600mg − Levetiracetam 4000mg
4.18 ( 2.08, 6.29)
<.001
Levetiracetam 4000mg − Placebo
-4.25 ( -6.76, -1.75)
0.001
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: Divided Attention (DA) Test : Percentage of Target Hits (%) - Emax –
Pharmacodynamic Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
0.18 ( -2.33, 2.70)
0.885
Retigabine 600mg − Placebo
0.04 ( -2.20, 2.28)
0.971
Retigabine 300mg − Alprazolam 1.5mg
2.00 ( -0.36, 4.36)
0.096
Retigabine 600mg − Alprazolam 1.5mg
1.86 ( -0.32, 4.04)
0.094
Retigabine 300mg − Alprazolam 3mg
2.31 ( 0.15, 4.47)
0.036
Retigabine 600mg − Alprazolam 3mg
2.17 ( 0.08, 4.26)
0.042
Alprazolam 1.5mg − Placebo
-1.82 ( -3.85, 0.22)
0.080
Alprazolam 3mg − Placebo
-2.12 ( -4.36, 0.11)
0.062
Retigabine 300mg − Levetiracetam 4000mg
0.91 ( -1.12, 2.94)
0.374
Retigabine 600mg − Levetiracetam 4000mg
0.77 ( -1.29, 2.83)
0.460
Levetiracetam 4000mg − Placebo
-0.73 ( -3.21, 1.75)
0.561
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
Analysis of Covariance: Divided Attention (DA) Test : Number of False Alarms – Emax – Pharmacodynamic
Population
Contrast
Mean of Difference (95% CI)
P-value
Retigabine 300mg − Placebo
2.2 ( -1.4, 5.8)
0.233
Retigabine 600mg − Placebo
2.7 ( -0.6, 5.9)
0.105
Retigabine 300mg − Alprazolam 1.5mg
-2.4 ( -5.7, 1.0)
0.163
Retigabine 600mg − Alprazolam 1.5mg
-1.9 ( -5.0, 1.2)
0.230
Retigabine 300mg − Alprazolam 3mg
-6.7 ( -9.7, -3.6)
<.001
Retigabine 600mg − Alprazolam 3mg
-6.2 ( -9.2, -3.2)
<.001
Alprazolam 1.5mg − Placebo
4.6 ( 1.6, 7.5)
0.003
Alprazolam 3mg − Placebo
8.8 ( 5.6, 12.0)
<.001
Retigabine 300mg − Levetiracetam 4000mg
-2.3 ( -5.3, 0.6)
0.112
Retigabine 600mg − Levetiracetam 4000mg
-1.9 ( -4.9, 1.1)
0.217
Levetiracetam 4000mg − Placebo
4.5 ( 1.0, 8.0)
0.012
Note: Least squares means were estimated from a linear mixed-effect analysis of covariance with treatment sequence,
period, and treatment as fixed effects, baseline (predose) value as a covariate, and subject within treatment sequence
as a random effect.
14
Pharmacokinetics (PK):
Summary of Pharmacokinetic Parameters: AUC(0-t) (ng*hr/mL): Per-Protocol Population
Retigabine
Retigabine 300mg
Retigabine 600mg
Retigabine 900mg
N=26
N=26
N=3
N
26
26
3
Mean (SD)
3988.2 (1333.09)
8756.4 (3508.55)
11914.8 (2640.51)
Median
3790.3
7605.5
11098.2
Geometric Mean
3776.4
8086.5
11728.9
Range
2214.1 to 6713.9
3778.2 to 15313.6
9779.0 to 14867.1
95% CI
3449.7, 4526.6
7339.3, 10173.5
5355.4, 18474.2
15
Safety results: Treatment-emergent adverse events (TEAEs) were defined as those AEs with onset after the initiation
of study drug and within 30 days after the last dose of study drug. Non-treatment-emergent AEs that occurred
between the time of signing the ICF and the first dose of study medication in the Treatment Phase were shown in the
AE listings but were not summarized or discussed further.
The Most Frequent 5 TEAEs That Occurred in Each Treatment Group
TEAE
Placebo
ALPR
ALPR
LEV
RTG
RTG
RTG
Placebo1
1.5mg
3mg
4000mg
300mg
600mg
900mg
N
26
28
29
30
33
34
6
25
No. subjects with
12 (46)
26 (93)
29 (100)
25 (83)
20 (61)
27 (79)
6 (100)
10 (40)
any AE, n (%)
Somnolence
4 (15)
16 (57)
28 (97)
10 (33)
6 (18)
5 (15)
4 (67)
2 (8)
Headache
7 (27)
5 (18)
1 (3)
8 (27)
7 (21)
9 (27)
3 (50)
5 (20)
Euphoric mood
2 (8)
1 (4)
5 (17)
12 (40)
6 (18)
7 (21)
2 (33)
0
Dizziness
0
1 (4)
1 (3)
10 (33)
4 (12)
3 (9)
1 (17)
0
Fatigue
0
8 (29)
2 (7)
3 (10)
1 (3)
5 (15)
1 (17)
0
Nausea
0
0
1 (3)
3 (10)
1 (3)
4 (12)
1 (17)
2 (8)
Eye disorders
0
0
2 (7)
1 (3)
0
3 (9)
3 (50)
1 (4)
Hiccups
0
2 (7)
3 (10)
0
0
0
0
0
Gait disturbance
0
0
1 (3)
3 (10)
0
0
0
0
Vision blurred
0
0
1 (3)
0
0
3 (9)
0
0
Visual disturbance
0
0
0
1 (3)
0
0
3 (50)
0
Amnesia
0
1 (4)
0
0
0
1 (3)
1 (17)
0
Dry mouth
0
0
0
1 (3)
1 (3)
0
1 (17)
0
Blood creatine
0
0
0
1 (3)
0
2 (6)
0
0
phosphokinase
increased
Disturbance in
0
0
0
0
0
2 (6)
0
0
attention
Memory
0
0
0
0
0
2 (6)
0
0
impairment
Hypoesthesia
1 (4)
0
0
0
0
0
1 (17)
0
Head discomfort
1 (4)
1 (4)
0
1 (3)
0
0
0
0
Anxiety
0
0
0
0
0
2 (6)
0
0
Confusional state
0
0
0
0
0
0
2 (33)
0
Hallucination
0
1 (4)
0
0
0
0
1 (17)
0
Bradyphrenia
0
0
0
0
0
0
1 (17)
0
Fear
0
0
0
0
0
0
1 (17)
0
Paranoia
0
0
0
0
0
0
1 (17)
0
Cardiac arrest2
0
0
0
0
0
0
1 (17)
0
Ventricular
0
0
0
0
0
0
1 (17)
0
tachycardia2
Early menarche
0
1 (4)
0
0
0
0
0
0
Diarrhea
0
1 (4)
0
0
0
0
0
0
Sluggishness
0
1 (4)
0
0
1 (3)
1 (3)
0
0
White blood cell
0
1 (4)
0
0
0
0
0
0
count increased
Insomnia
0
1 (4)
0
0
0
0
0
0
Feeling of
0
0
1 (3)
0
1 (3)
0
0
0
relaxation
Irritability
1 (4)
0
1 (3)
0
1 (3)
1 (3)
0
0
Nasal congestion
0
0
1 (3)
1 (3)
0
0
0
0
Paraesthesia oral
0
0
0
0
1 (3)
1 (3)
0
0
Heart rate
0
0
0
0
1 (3)
0
0
0
increased
Muscular
0
0
0
0
1 (3)
0
0
0
weakness
16
Sensation of
0
0
0
0
1 (3)
0
0
0
heaviness
Burning sensation
0
0
0
0
1 (3)
0
0
0
Dysarthria
0
0
0
0
1 (3)
1 (3)
0
0
Lethargy
0
0
0
0
1 (3)
0
0
0
Paraesthesia
0
0
0
0
1 (3)
1 (3)
0
0
Agitation
0
0
0
0
1 (3)
0
0
0
Hypervigilance
0
0
0
1 (3)
1 (3)
0
0
0
Pollakiuria
0
0
0
0
1 (3)
0
0
0
Dry throat
0
0
0
0
1 (3)
0
0
0
Pharyngolaryngeal
0
0
0
1 (3)
1 (3)
0
0
0
pain
Tachycardia
0
0
0
0
0
0
0
1 (4)
Photophobia
0
0
0
0
0
0
0
1 (4)
Abdominal pain
0
0
0
1 (3)
0
1 (3)
0
1 (4)
Hypoaesthesia oral
0
0
0
0
0
1 (3)
0
1 (4)
Dysmenorrhea
0
0
0
0
0
0
0
1 (4)
Rhinorrhea
0
0
0
0
0
0
0
1 (4)
Pruritus
0
0
0
0
0
0
0
1 (4)
Rash
0
0
0
0
0
1 (3)
0
1 (4)
ALPR = Alprazolam
LEV = Levetiracetam
RTG = Retigabine
1. Placebo refers to the subject that received placebo in substitution for 900mg retigabine
2. Both “Cardiac Disorders” TEAEs (cardiac arrest and ventricular tachycardia) were considered SAEs. Both events
resolved spontaneously without sequelae.
Serious Adverse Events (Treatment-Emergent), n (%) [n considered by the investigator to be related, possibly
related, or probably related to study medication]:
Placebo ALPR
ALPR
LEV
RTG
RTG
RTG
Placebo1
1.5mg
3mg
4000mg 300mg 600mg
900mg
N (Safety Population)
26
28
29
30
33
34
6
25
No. subjects with any
0
0
0
0
0
0
2 (33.3)[2]
0
SAE, n (%)
Ventricular
0
0
0
0
0
0
1 (16.7)[1]
0
tachycardia2
Cardiac arrest2
0
0
0
0
0
0
1 (16.7)[1]
0
ALPR = Alprazolam
LEV = Levetiracetam
RTG = Retigabine
1. Placebo refers to the subject who received placebo in substitution for 900mg retigabine)
2. Both cardiac SAEs resolved spontaneously without sequelae. The episode of cardiac arrest/asystole did not
require any resuscitation procedure. Both cardiac SAEs were of short duration and documented by telemetry. The
12 lead ECGs performed at pre dose, 2.5 hrs and 6.5 hrs after each dose did not show clinically significant
findings in either the subjects with SAEs or in the overall study population. For this reason, the results of the 12
lead ECGs conducted as part of the overall safety evaluation are not reported in this study summary.
17