The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.:MPX111381 Title: A dose-ranging study evaluating the efficacy, safety and tolerability of Gabapentin enacarbil (/XP13512/GSK1838262 ) in the prophylactic treatment of migraine headache Rationale: is an actively transported prodrug of gabapentin that provides dose proportional and sustained exposure of gabapentin. Unlike orally administered gabapentin, which is absorbed by low capacity transporters expressed in a limited region of the upper intestine, is absorbed by high capacity transport mechanisms present throughout the gastrointestinal tract, including the colon. As a result, is well absorbed and provides rapid and extended delivery of gabapentin into the systemic circulation. offers dose-proportional gabapentin exposure, predictable absorption, and the opportunity to optimize gabapentin exposure to subjects. Additionally, is administered as an extended release formulation, providing twice daily administration in subjects (e.g., compared to three times a day administration with Neurontin). The purpose of study MPX111381 was to evaluate the dose response relationship, efficacy, safety and tolerability of target doses of 1200, 1800, 2400 and 3000 compared with placebo in the prophylactic treatment of migraine headache. Phase: IIB Study Period: 26 Aug 2008-02Jun 2010 Study Design: Multicenter, randomized, double-blind, placebo-controlled, parallel group, flexibledose evaluation of 1200, 1800, 2400 and 3000 compared with placebo in the prophylactic treatment of migraine headache. The study consisted of six study periods for a total study duration of up to 30 weeks: Screening (2 weeks), baseline (including randomization, 6 weeks), flexible titration (5 weeks), maintenance (12 weeks), taper (3 weeks) and post-treatment (2 weeks). The flexible titration administration of investigational product was designed to allow subjects to reach the target dose for maintenance treatment or, if unable to reach this target dose, to achieve a maximum tolerated dose for maintenance treatment. In addition, subjects had the opportunity to undergo a single dose (600 /day) downward adjustment during the flexible titration period if intolerability at the current dose occurred. Subsequently, if a single dose downward adjustment occurred, no further dose adjustments in the study (upward or downward) were permitted. Treatment groups were designated by their target dose regardless of the maximum tolerated dose achieved. Centres: Subjects were randomized to 51 centers in the US and Canada Indication: Treatment: Investigational product was supplied as a free acid formulated as an oral, extendedrelease, white to off-white tablet containing 600 or matching placebo. Objectives: The objectives of the study were to evaluate the dose response relationship, efficacy, safety and tolerability profile of target doses of 1200 /day, 1800 /day, 2400 /day and 3000 /day compared with placebo in the prophylactic treatment of migraine headache in adults. Primary Outcome/Efficacy Variable: The primary endpoint was the change from baseline in the number of migraine headache days (MHD) during the last 4 weeks of treatment prior to taper. 1
Secondary Outcome/Efficacy Variable(s): For the 5-week flexible titration phase, the first, second and third 4-week segments of the maintenance phase, the entire maintenance phase, the entire treatment phase and the last 4 weeks of treatment prior to taper, the secondary clinical efficacy endpoints included: 1. Change from baseline in the number of MHD (for all study phases except for the last 4 weeks of treatment prior to taper which is the primary endpoint). 2. Change from baseline in the number of migraine attacks. 3. Change from baseline in the number of migraine headache periods. 4. Change from baseline in mean migraine attack duration. 5. Change from baseline in the mean peak migraine pain severity (utilizing the 4-point pain scale). 6. Change from baseline in acute migraine medication use compared to placebo including type of medication, number of days of medication use, and number of doses. 7. Change from baseline in percent of migraine attacks with each of the following migraine symptoms: aura, nausea, vomiting, photophobia, phonophobia. 8. Percent of responders (e.g., subjects that achieve at least a 50% reduction) for each of the following measures: MHD, migraine attacks and migraine headache periods. The following clinical endpoint was defined and assessed at various time points during the course of treatment: The proportion of subjects who were much improved or very much improved on the Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC). The following secondary health outcomes endpoints were assessed: Change from baseline in Migraine Specific Quality of Life Questionnaire Version 2.1 (MSQ v2.1) subscales (role function-restrictive, role function-preventive, emotional function). Change from baseline in the Headache Impact Test-6 item (HIT-6) test scores. Productivity as measured by lost time equivalents (LTE), which was a composite measure of presenteeism (continued to work while under the influence of migraine symptoms) and absenteeism (time missed from work due to migraine). LTE was applied to productivity for work and non-work activities. Treatment satisfaction measured using 3-global items: satisfaction with overall medication effectiveness, satisfaction with side effects and overall satisfaction. Statistical Methods: A total of 528 subjects were planned to be randomized to treatments of placebo: 1200 /day: 1800 /day: 2400 /day: 3000 /day in a 2:1:2:2:1 ratio. The primary comparison was based on the average of 1800 and 2400 versus placebo using the Intent-to-Treat (ITT) Population. The Safety Population, used to assess safety endpoints, was composed of all subjects who took at least a partial dose of investigational product. The ITT Population, used to assess all efficacy endpoints, was comprised of all randomized subjects who took at least one tablet of investigational product and provided at least 2
one post-baseline efficacy measurement. The Per Protocol (PP) Population, which excluded subjects in the ITT Population with major protocol violations, was used in a sensitivity analysis of the primary endpoint to confirm the findings of the primary analysis. The primary endpoint was the change from baseline in number of MHD during the last 4 weeks of treatment prior to taper. For each day of missing data during the last 4 weeks of treatment, the 4- week window was extended earlier into the treatment period until there were 28 days of nonmissing diary data. For endpoints assessed as a change from baseline, including the primary efficacy endpoint, each dose of (or the average of 1800 and 2400 ) was compared with placebo using a parametric Analysis of Covariance (ANCOVA) model, with baseline score for the endpoint being analyzed, International Headache Society (IHS) Headache Classification for the presence or absence of aura, and randomized treatment as terms in the model. The responder analyses (for percent reduction in MHD, migraine attacks, and migraine headache periods (MHP) were analyzed by comparing the percent of subjects with at least a 50% reduction to the percent of those with a lesser reduction, using a chi-square test stratified by IHS Headache Classification for the presence or absence of aura. The Kolmogorov-Smirnov test was used to compare the cumulative distribution of the percent reduction from baseline. A non-parametric ANCOVA was used to analyze the percent of migraine attacks with each symptom (i.e., nausea, vomiting, photophobia, phonophobia, and aura). The PGIC and CGIC responder endpoints (i.e., proportion of subjects who were much improved or very much improved ) were analyzed using logistic regression with baseline number of MHD and randomized treatment as terms in the model. Study Population: For the purposes of this study, subjects were required to experience at least three migraines (with or without aura according to the 2004 IHS criteria 1.1 and 1.2.1) per month during the last 3 months prior to screening, with a history of migraine headache for at least one year with consistent migraine headache over time (i.e., incidence and severity). In addition, subjects had to have at least three headache attacks per month during the 3 months prior to screening and at least four migraine headache days but less than 15 total headache days (migraine or non-migraine) per month during the 3 months prior to screening and must have maintained this requirement throughout the last 4 weeks of the baseline period. Subjects who in the investigators judgment, failed more than two adequate treatments of migraine prophylaxis where failure was defined as a lack of efficacy with treatment duration of at least 8 weeks were not eligible for participation in the trial. Subjects who took gabapentin or pregabalin previously for the prophylactic treatment of migraine headache were not eligible, although subjects who took these medications for the treatment of other conditions were allowed in the trial if the total exposure was less than three months during the past 12 months and the medication was stopped at least three months prior to baseline. Subject were excluded from participation if there was any history of ergotamine, triptan, opioid, and/or combination pain medication use 10 days per month on a regular basis for 3 months. Subjects were also excluded if they were unable to discontinue prohibited medications during the 2 week-screening period and throughout the duration of the study. Since the concentration of gabapentin, the active moiety of, in the serum is increased with impaired renal function, subjects with a creatinine clearance <60 ml/min., or renal dysfunction requiring hemodialysis, were excluded. Placebo 1200 1800 2400 Number of Subjects: Planned, N 132 66 132 132 66 Randomized, N 129 67 134 134 62 Completed, n (%) 95 (74) 49 (73) 88 97 37 3000 3
(66) (72) (60) Total Number Subjects Withdrawn, n (%) 34 (26) 18 (27) 46 (34) 37 (28) 25 (40) Withdrawn due to Adverse Events n (%) 11 (9) 4 (6) 17 (13) 16 (12) 13 (21) Withdrawn due to Lack of Efficacy n 6 (5) 1 (1) 1 (<1) 3 (2) 1 (2) (%) Withdrawn due to Withdrew Consent 8 (6) 4 (6) 14 7 (5) 37 (7) n (%) (10) Withdrawn due to Protocol Deviation 6 (5) 5 (7) 4 (3) 5 (4) 3 (5) n (%) Withdrawn due to Lost to follow-up n 3 (2) 4 (6) 5 (4) 5 (4) 3 (5) (%) Withdrawn due to Investigator 0 0 5 (4) 1 (<1) 1 (2) discretion n (%) Demographics N (ITT Population) 128 66 134 133 62 Females: Males n (%) 111 (87):17 (13) 52 (79):14 (21) 11C5 (86):1 105 (79):2 46 (74):1 9 ( Mean Age, years (SD) 41.1 (11.72) 39.4 (9.74) 37.7 (11.75 ) Race White n(%) 108 (84) 54 (82) 107 (80) Primary Efficacy Results: Change from Baseline in the Number of MHD Placebo Avg of 1800 and 2400 1800 2400 8 (21) 39.0 (12.0 4) 112 (84) 1200 6 (26) 39.1 (11.7 8) 53 (85) 3000 n (ITT Population) 128 261 131 130 63 62 Adjusted mean change from Baseline (SE) to the Last 4-Week Treatment Phase -3.8 (0.38) -3.6 (0.26) -3.8 (0.37) -3.3 (0.37) -3.2 (0.53) -3.6 (0.54 ) Treatment difference vs placebo - 0.3 0.0 0.5 0.6 0.3 95% CI - (-0.6, 1.1) (-1.3, 1.3) (-0..8, 1.8) (-1.0, 2.2) (-1.4, 1.9) Adjusted p-value - 0.579 >0.99 0.783 0.775 0.987 9 Secondary Outcome Variable(s): Placebo 1200 1800 2400 3000 N (ITT Population) 128 66 134 133 62 Number of Migraine Headache Days (MHD) for all study phases, excluding the Last 4WK TRT n 124 59 119 124 59 Mean Change from Baseline in the # of migraine headache days Baseline to Titration -2.434-1.920-2.431-2.573-2.325 SE 0.3621 0.5224 0.3375 0.3352 0.5055 4
Median -2.652-2.234-2.667-2.587 =2.667 n 124 59 119 124 59 Mean Change from Baseline in the -3.147-2.191-3.424-3.419-2.974 # of migraine headache days Baseline to 1st 4-Week segment of maintenance phase SE 0.4043 0.6758 0.3204 0.3941 0.5522 Median -3.667-2.720-3.259-4.241-3.350 n 124 59 119 124 59 Mean Change from Baseline in the -3.595-2.739-3.953-3.360-3.520 # of migraine headache days Baseline to 2 nd 4-Week segment of maintenance phase SE 0.3784 0.6897 0.3794 0.4201 0.5669 Median -3.966-3.185-4.000-4.000-4.053 n 124 59 119 124 59 Mean Change from Baseline in the -3.865-3.171-3.988-3.439-3.220 # of migraine headache days Baseline to 3 rd 4-Week segment of maintenance phase SE 0.3992 0.6660 0.3810 0.4483 0.6594 Median -4.000-4.000-4.000-4.076-4.497 n 112 54 101 107 45 Mean Change from Baseline in the -3.846-2.854-4.047-3.794-3.723 # of migraine headache days Baseline to Maintenance phase SE 0.3589 0.6565 0.3368 0.3761 0.6492 Median -3.764-3.465-4.000-3.782-4.729 n 118 56 113 118 56 Mean Change from Baseline in the -3.396-2.834-3.579-3.393-3.193 # of migraine headache days Baseline to Treatment phase SE 0.3422 0.5640 0.3140 0.3388 0.5165 Median -3.250-2.887-3.559-3.285-4.345 Number of Migraine Attacks N 120 59 114 123 58 Mean Change from Baseline to the -2.2-2.2-2.3-2.1-2.6 SE 0.15 0.22 0.16 0.15 0.22 Treatment difference vs. placebo - -0.1-0.2 0.0-0.4 95% CI - (-0.7, 0.6) (-0.7, 0.3) (-0.5, 0.6) (-1.1, 0.2) Number of Migraine Headache Periods n 120 59 114 123 58 Mean Change from Baseline to -3.3-3.0-3.6-3.0-3.2 the SE 0.35 0.50 0.36 0.34 0.50 Treatment difference vs. placebo - 0.3-0.3 0.3 0.0 95% CI (-1.2, 1.8) (-1.5, 0.9) -0.9, 1.5) (-1.5, 1.5) 5
Migraine Symptoms and Characteristics Mean Migraine Attack Duration (Hours) Mean Change from Baseline to -0.97 3.01-2.93 2.59 9.82 Last 4-week treatment phase SE 3.355 5.720 3.658 5.000 9.975 Median Change from Baseline to -4.41-0.57-4.79-3.65-4.53 Last 4-week treatment phase 95% CI for Median (-8.7, 2.5) (-6.5, 5.7) (-10.6, 0.0) (-8.8, 5.9) (-9.7, 11.4) Mean Peak Migraine Pain Severity Mean Change from Baseline to the -0.12-0.13-0.12-0.04-0.09 SE 0.058 0.086 0.055 0.050 0.080 Median Change from Baseline to 0.00-0.04 0.00 0.00 0.00 Last 4-week treatment phase 95% CI for Median (-0.2, 0.0) (-0.3, 0.0) (-0.2, 0.0) (-0.1, 0.0) (-0.3, 0.1) Acute Migraine Medications Number of Days of acute migraine medication use n 120 59 114 123 58 Mean change from Baseline to the -2.0-2.3-2.7-2.2-2.1 SE 0.28 0.39 0.28 0.27 0.40 Treatment difference vs. placebo - -0.3-0.7-0.3-0.1 95% CI - (-1.5, 0.9) (-1.7, 0.2) (-1.2, 0.7) (-1.3, 1.1) Number of Acute Migraine Medication Doses Administered n 120 59 114 123 58 Mean change from Baseline to the -4.5-4.8-5.8-5.1-4.5 SE 0.69 0.97 0.70 0.67 0.98 Treatment difference vs. placebo - -0.3-1.2-06 0.0 95% CI - (-3.2, 2.7) (-3.6, 1.2) (-3.0, 1.8) (-2.9, 3.0) Number of acute migraine medication doses administered by Triptan use Triptan User N 75 32 70 65 35 n 72 30 65 63 32 Mean Change from Baseline to the -3.3-2.9-4.9-4.3-2.6 SE 0.88 1.35 0.91 0.93 1.31 Treatment difference vs. placebo - 0.4-1.6-1.0 0.7 95% CI - (-2.8, 35) (-4.1, 0.9) (-3.5, (-2.4, 6
1.5) 3.8) Not a Triptan User N 53 34 64 68 27 n 48 29 49 60 26 Mean Change from Baseline to the -6.3-6.7-6.9-6.0-68 SE 1.06 1.36 1.05 0.95 1.44 Treatment difference vs. placebo - -0.4-0.6 0.3-0.5 95% CI - (-3.8, 3.0) (-3.6, 2.3) (-2.5, 3.1) (-4.0, 3.0) Number of acute migraine medication doses administered by Opioid use Opioid User N 22 8 16 26 11 n 20 7 14 26 10 Mean Change from Baseline to the -1.7 1.4-3.2-6.0-5.1 SE 1.66 2.81 1.97 1.45 2.34 Treatment difference vs. placebo - 3.1-1.4-4.2-3.3 95% CI - (-3.3, 9.5) (-6.5, 3.6) (-8.6, 0.1) (-9.0, 2.3) Non-opioid User N 106 58 118 107 51 n 100 52 100 97 48 Mean Change from Baseline to the -5.1-5.7-6.2-4.9-4.4 SE 0.75 1.03 0.74 0.75 1.08 Treatment difference vs. placebo - -0.6-1.1 0.2 0.7 95% CI - (-3.1, 1.9) (-3.1, 1.0) (-1.9, 2.2) (-1.9, 3.2) Number of acute migraine medication doses administered by Prescription Headache Medication use Uses Prescription HA meds N 93 40 87 90 42 n 89 38 80 88 39 Mean Change from Baseline to the -3.6-3.5-4.9-4.0-3.3 SE 0.78 1.19 0.82 0.78 1.18 Treatment difference vs. placebo - 0.1-1.3-0.4 0.3 95% CI - (-2.6,.29) (-3.5, 0.9) (-2.5, 1.8) (-2.4, 3.1) Uses OTC HA meds Only N 35 26 47 43 20 n 31 21 34 35 19 Mean Change from Baseline to -6.9-7.2-7.8-7.9-6.9 the SE 1.31 1.59 1.25 1.23 1.68 Treatment difference vs. placebo - -0.2-0.9-1.0 0.0 95% CI - (-4.3, 3.8) (-4.4, 2.7) (-4.5, 2.6) (-4.2, 4.2) Migraine Attacks 7
Percent of Migraine Attacks with Aura Mean Change from Baseline to -7.04-3.37-7.43-0.72 1.21 the SE 3.640 4.834 3.230 3.044 4.372 Percent of Migraine Attacks with Nausea Mean Change from Baseline to the -8.0-2.0-5.2-0.5 5.0 SE 3.73 5.74 3.87 3.46 4.69 Percent of Migraine Attacks with Vomiting Mean Change from Baseline to 0.0-0.9-0.4 3.7 0.4 the SE 2.60 2.98 3.01 3.07 4.83 Percent of Migraine Attacks with Photophobia Mean Change from Baseline to the -1.9-3.5-2.1-5.5 0.1 SE 2.82 4.09 2.86 2.64 2.49 Percent of Migraine Attacks with Phonophobia Mean Change from Baseline to -5.4 1.2-0.7-7.4 3.6 the SE 3.14 3.05 3.42 2.88 1.93 Responder rates for Number of Migraine Headache Days n 120 59 114 123 58 Percentage Reduction from Baseline to Last 4-Week Treatment phase >=0 96 (80) 48 (81) 100 (88) 99 (80) 47 (81) >=10% 91 (76) 48 (81) 94 (82) 92 (75) 46 (79) >=20% 81 (68) 44 (75) 90 (79) 91 (74) 43 (74) >=30% 80 (67) 35 (59) 83 (73) 84 (68) 42 (72) >=40% 74 (62) 31 (53) 78 (68) 73 (59) 39 (67) >=50% 65 (54) 26 (44) 68 (60) 67 (54) 38 (66) >=60% 59 (49) 26 (44) 54 (47) 51 (41) 34 ( 59) >=70% 45 (38) 23(39) 46 (40) 46 (37) 28 ( 48) >=80% 36 (30) 17 (29) 40 (35) 32 (26) 22 (38) >=90% 29 (24) 13 (22) 34 (30) 23 (19) 16 (28) 100% 27 (23) 12 (20) 34 (30) 22 (18) 16 (28) Responder rates for Number of Migraine Attacks n 120 59 114 123 58 Percentage Reduction from Baseline to Last 4-Week Treatment phase >=0 109 (90) 54 ( 92) 103 (90) 112 (91) 51 (88) >=10% 93 (78) 52 (88) 96 (84) 98 (80) 48 (83) >=20% 91 (76) 49 *93) 94 (82) 97 (79) 46 (79) 8
>=30% 82 (68) 42 (71) 85 (75) 80 (65) 43 (74) >=40% 75 (63) 37 (63) 78 (68) 72 (59) 43 (74) >=50% 64 (53) 31 (53) 67 (59) 67 (54) 39 (67) >=60% 50 (42) 27 (46) 59 (52) 55 (45) 32 (55) >=70% 35 (29) 21 (36) 46 (40) 34 (28) 25 (43) >=80% 29 (24) 16 927) 37 (32) 25 (20) 18 (31) >=90% 28 (23) 12 (20) 34 (30) 24 (20) 17 (29) 100% 28 (23) 12 (20) 34 (30) 24 (20) 17 (29) Responder rates for Number of Migraine Headache Periods n 120 59 114 123 58 Percentage Reduction from Baseline to Last 4-Week Treatment phase >=0 94 (78) 50 (85) 101 (89) 98 (80) 47 (81) >=10% 88 (73) 47 (80) 97 (85) 96 (78) 44 (76) >=20% 85 (71) 42 (71) 89 (78) 93 (76) 43 (74) >=30% 80 (67) 38 (64) 83 (73) 86 (70) 42 (72) >=40% 71 (59) 36 (61) 75 (66) 76 (62) 40 (69) >=50% 65 (54) 27 (46) 70 (61) 69 (56) 40 (69) >=60% 55 (46) 25 (42) 63 (55) 55 (45) 35 (60) >=70% 43 (36) 23(39) 48 (42) 49 (40) 29 (50) >=80% 35 (29) 18 (31) 40 (35) 33 (27) 20 (34) >=90% 30 (25) 12 (20) 34 (30) 23 (19) 16 (28) 100% 27 (23) 12 (20) 34 (30) 23 (19) 16 (28) Proportion of Subjects who are much improved or very much improved on the PGIC Week 17 71/123 (58%) 40/57 (70%) 84/115 (73%) 81/121 (67%) 36/55 (65%) Adjusted Odds Ratio - 1.7 2.0 1.5 1.4 95% CI - (0.9, 3.4) (1.2, 3.4) (0.9, 2.5) (0.7, 2.7) Proportion of Subjects who are much improved or very much improved on the CGIC Week 17 75/124 (60%) 40/57 (70%) 84/116 (72%) 85/120 (71%) 32/55 (58%) Adjusted Odds Ratio - 1.5 1.76 1.6 0.9 95% CI - (0.8, 3.0) (1.0, 3.0) (0.9, 2.7) (0.5, 1.7) Migraine Specific Quality of Life (MSQ v2.1) Role Function Restrictive n 120 57 115 121 54 Mean change from Baseline to 30.7 38.7 37.1 32.8 30.9 Week 17 SE 2.3 3.1 2.4 2.3 3.7 Treatment difference vs. Placebo - 8.0 6.4 2.1 0.1 95% CI - (-1.6, 17.5) (-1.8, 14.6) (-5.9, 10.1) (-10.7, 11.0) Role Function Preventive n 120 57 115 121 62 Mean change from Baseline to Week 17 22.7 28.6 28.0 23.9 22.4 9
SE 2.0 2.7 2.0 2.0 3.2 Treatment difference vs. Placebo - 6.0 5.4 1.2-0.3 95% CI - (-2.2, 14.2) (-1.7, 12.4) (-5.7, 8.1) (-9.6, 9.0) Emotional Function n 120 57 115 121 54 Mean change from Baseline to 29.7 37.0 34.8 30.4 25.7 Week 17 SE 2.6 3.5 2.6 2.5 4.1 Treatment difference vs. placebo - 7.3 5.2 0.8-3.9 95% CI - (-3.3, 18.0) (-3.9, 14.3) (-8.9, 9.7) (-15.9, 8.1) Headache Impact Test (HIT-6) Total Score n 119 57 114 131 54 Mean change from Baseline to -10.0-12.2-11.8-9.8-10.3 Week 17 SE 0.95 1.28 0.98 0.94 1.53 Treatment difference vs. placebo - -2.2-1.8 0.2-0.3 95% CI - (-6.1, 1.7) (-5.2, 1.5) (-3.1, 3.5) (-4.7, 4.2) Lost Productivity Lost Time Equivalents for Work Activities (LWP) n 52 23 41 35 17 Mean change from Baseline to the -0.8-0.3-0.9-0.1 0.8 Last 4-week Treatment phase SE 0.49 0.73 0.55 0.59 0.85 Treatment difference vs. placebo - 0.5-0.1 0.7 1.6 95% CI - (-1.7, 2.7) (-2.0, 1.7) (-1.2, 2.6) (-0.9, 4.0) Lost Time Equivalents for Non- Work Activities (LAT) Mean change from Baseline to the -0.1-0.1-1.2-1.0 1.7 Last 4-week Treatment phase SE 0.74 1.02 0.78 0.73 1.11 Treatment difference vs. placebo - -0.2-1.3-1.1 1.6 95% CI - (-3.3, 2.9) (-3.9, 1.4) (-3.6, 1.6) (-1.7, 4.9) Lost Time Equivalents for Work and Non-Work Activities (LTE) in hours Mean change from Baseline to the -0.2-0.5-1.7-1.1 2.1 Last 4-week Treatment phase SE 0.83 1.14 0.87 0.82 1.24 Treatment difference vs. placebo - -0.2-1.5-0.9 2.3 95% CI - (-3.7, 3.2) (-4.4, 1.5) (-3.7, 2.0) (-1.3, 6.0) Level of Treatment Satisfaction Treatment Satisfaction: How effective was the medication overall (Week 17) 10
Satisfied (includes subjects who reported being very satisfied and satisfied ) n (%) Adjusted Probability of being 74/123 (60%) 39/57 (68%) 84/118 (71%) 81/120 (68%) 36/54 (67%) 0.602 0.682 0.714 0.679 0.662 Satisfied Adjusted odds ratio - 1.4 1.7 1.4 1.3 95%CI - (0.7, 2.8) (1.0, 2.8) (0.8, 2.4) (0.7, 2.5) Treatment Satisfaction: Side Effects of the medication (Week 17) Satisfied (includes subjects who reported being very satisfied and satisfied ) n (%) 79/123 (64%) 32/57 (56%) 72/118 (61%) 75/120 (63%) 28/54 (52%) Adjusted Probability of being 0.643 0.558 0.612 0.628 0.513 Satisfied Adjusted odds ratio - 0.7 0.9 0.9 0.6 95% CI - (0.4, 1.3) (0.5, 1.5) (0.6, 1.6) (0.3, 1.1) Treatment Satisfaction: Overall satisfaction with medication Satisfied (includes subjects who reported being very satisfied and satisfied ) n (%) 76/123 (62%) 39/57 (68%) 84/118 (71%) 84/120 (70%) 34/54 (63%) Adjusted Probability of being 0.619 0.682 0.714 0.704 0.625 Satisfied Adjusted odds ratio - 1.3 1.5 1.5 1.0 95% CI - (0.7, 2.6) (0.9, 2.6) (0.9, 2.5) (0.5, 2.0) Period of collection of on therapy AEs and SAEs The following Adverse Events (AEs) were considered treatment-emergent: AEs beginning during treatment (including up to 1 day after the last dose); AEs beginning prior to the 1 st dose of study medication but worsening after the 1 st dose of study medication Placebo 1200 1800 2400 Most Common (>=5%) Non-Serious Treatment Emergent Adverse Events N (Safety Population) 128 66 134 133 62 Subjects with any AE(s), n(%) 87 (67) 44 (67) 99 (74) 101 (76) 47 (76) Dizziness 8 (6) 16 (24) 43 (32) 35 (26) 11 (18) Fatigue 9 (7) 10 (15) 12 (9) 14 (11) 3 (5) Nausea 12 (9) 3 (5) 15 12 (9) 6 (10) (11) Somnolence 6 (5) 6 (9) 7 (5) 14 (11) 9 (15) Weight increased 7 (5) 4 (6) 8 (6) 9 (7) 4 (6) Upper respiratory tract infection 9 (7) 4 (6) 4 (3) 9 (7) 5 (8) Constipation 3 (2) 4 (6) 7 (5) 8 (6) 5 (8) Dry mouth 3 (2) 10 (15) 12 (9) 14 (11) 3 (5) Nasopharyngitis 8 (6) 3 (5) 4 (3) 4 (3) 2 (3) Diarrhoea 8 (6) 1 (2) 1 (<1) 7 (5) 1 (2) Vomiting 5 (4) 1 (2) 3 (2) 7 (5) 2 (3) Influenza 4 (3) 1 (2) 3 (2) 4 (3) 3 (5) Insomnia 1 (<1) 4 (6) 3 (2) 4 (3) 3 (5) 3000 11
Oedema peripheral 4 (3) 4 (6) 1 (<1) 3 (2) 2 (3) Sinusitis 3 (2) 4 (6) 3 (2) 3 (2) 1 (2) Balance disorder 1 (<1) 2 (3) 2 (1) 6 (5) 1 (2) Abdominal pain 1 (<1) 2 (3) 2 (1) 3 (2) 3 (5) Back pain 0 1 (2) 6 (4) 1 (<1) 3 (5) Cough 0 3 (5) 1 (<1) 0 0 Serious Adverse Events - On-Therapy Placebo 1200 1800 2400 3000 Subjects with non-fatal TESAEs, n (%) N (Safety Population) 128 66 134 133 62 Any Event, n 2 0 2 0 4 Appendicitis 0 0 1 (<1) 0 0 Pharyngitis 1 (<1) 0 0 0 0 Pneumonia 0 0 0 0 1 (2) Cholecystitis 0 0 1 (<1) 0 0 Cholelithiasis 0 0 1 (<1) 0 0 Muscle spasms 1 (<1) 0 0 0 0 Metastatic malignant melanoma 0 0 0 0 1 (2) Convulsion 0 0 0 0 1 (2) Conversion disorder 0 0 0 0 1 (2) Subjects with fatal SAEs, (All Subjects pop) n (%) N (Safety Population) 128 66 134 133 62 Any Event, n 0 0 1 1 0 Bronchopneumonia 0 0 1 0 0 Accidental overdose 0 0 0 1 0 Conclusion: There was no difference found for any of the treatment groups compared to placebo on the primary endpoint [change from baseline during the last 4 week treatment phase (prior to taper) in the number of MHD]. A high placebo effect was noted in this study; this needs to be considered when interpreting the lack of effect of over placebo seen in this study. Although formal hypothesis testing of the secondary endpoints was not conducted, non-inferential testing of the secondary endpoints was consistent with the lack of separation shown in the primary endpoint. Safety and tolerability data did not reveal any new safety signals or trends related to exposure. 12