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. GSK Medicine: Camicinal, (040) Study Number: MOT115816 Title: A randomized, double-blind, placebo-controlled, parallel group, dose ranging study to assess the effect of repeat doses of 040 on the pharmacokinetics of L-DOPA in subjects with Parkinson s disease exhibiting delayed gastric emptying. Rationale: The main aim of this study was to determine if repeat administration of camicinal, through its ability to facilitate efficient gastric emptying, improves the absorption and pharmacokinetic profile of a given dose of L-DOPA resulting in improved Parkinson s symptom control as reflected by decreased OFF time and decreased Parkinson s disease motor symptoms. Phase: 2a Study Period: 06 Jul 2012 1 May 2014 Study Design: This was a repeat dose, multicentre, randomised, parallel-group, double-blind, placebo-controlled study. The study consisted of a screening period of up to 21 days, a 7-9 day treatment period, and a 14 day follow-up period. Centres: 11 Centres globally; 3 sites UK, 6 sites Germany, 1 site Sweden and 1 site Australia Indication: Camicinal is under investigation as an adjunctive treatment of motor symptom fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor therapy in adult patients with Parkinson's disease Treatment: Participants received placebo or camicinal 50 milligrams () (except for one participant who received camicinal 125 ) administered orally once daily for 7 to 9 days. Objectives: The primary objective of this study was to estimate the relationship between co-administration of camicinal on L-DOPA pharmacokinetic exposure in subjects with Parkinson s disease and slow or delayed gastric emptying. The secondary objectives were to measure the effect of camicinal on gastric emptying (GE); to determine the effect of camicinal on motor symptoms and amount of OFF time, to evaluate the safety and tolerability profile of co-administration of camicinal and L-DOPA; to evaluate the PK profile of camicinal Primary Outcome (Endpoints)/Efficacy : L-DOPA PK at screening (baseline), Days 1 and 8: dose-normalized AUC(0-4), dose-normalized Cmax, Tmax, t½ Secondary Outcome (Endpoints)/Efficacy : GE at screening (baseline), Days 1 and 8, as measured by the 13 C oral breath test (OBT (GE t½)) The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor and nonmotor score at screening (baseline), Days 1 and 8 Amount of awake time (in hours) spent ON, ON with troublesome dyskinesias, and OFF at screening (baseline), Days 1 through 8 Change in number of times subject can alternatively tap two (2) counter keys 30 cm apart in 1 minute during visit assessment (finger tapping). L-DOPA dose level and/or dosing frequency changes Vital signs, ECG, clinical laboratory data and adverse events Camicinal PK on Days 1 and 8: AUC, Cmax, tmax Statistical Methods: All safety analyses were performed on the All Subjects population which included all subjects who received at least one dose of study medication, i.e. placebo, camicinal 50 or camicinal 125. All pharmacodynamics, efficacy and pharmacokinetics analyses were performed on the Pharmacodynamic and Efficacy population which included all subjects who received at least one dose of placebo or camicinal 50. Prior to protocol amendment 4, one subject received camicinal 125. This subject was therefore excluded from all pharmacodynamics, efficacy and pharmacokinetics analyses. An estimation approach was used for all endpoints (except L-DOPA Tmax, which was analysed using a nonparametric method).confidence intervals were therefore calculated for the difference (or ratio) between camicinal 50 and placebo for each endpoint. Confidence intervals which do not contain 0 (or 1) indicate that the difference (or ratio) is statistically significant. The planned sample size of N=45 (N=30 for the camicinal 50 group, N=15 for the placebo group) was statistically powered (90% power, 5% alpha) to detect a 1.5 fold change in the mean AUC(0-4 hrs) (i.e. ratio of mean AUC(0-4 hrs) in camicinal 50 to mean AUC(0-4hrs) in placebo is 1.5). 1
Primary Outcome L-DOPA dose-normalised AUC(0-t) (t=0.5, 1.0, 1.5, 2.0, 2.5, 3.0. 3.5, 4.0 hours) and Cmax: The nominal parameters values were normalised to the L-DOPA dose taken just prior to dosing. Following loge-transformation, the parameters were statistically analysed by a mixed model fitting treatment, visit and the interaction as fixed effects, and subject as a random effect grouped by treatment. Baseline measurements of L-DOPA PK parameters and gastric half emptying time (GE t1/2) were included as covariates. The ratio of geometric means of camicinal to placebo for Day 1 and Day 8 was derived from the model. A ratio > 1 indicates higher exposure in the camicinal 50 group compared to placebo. Tmax: the change from baseline was derived for Day 1 and Day 8 and analysed separately for each visit using a Wilcoxon Rank-sum test. T1/2: This endpoint was not assessed because there were insufficient L-DOPA data/profiles to calculate this parameter. Secondary outcomes Gastric emptying t1/2: The change from baseline in gastric half emptying time (GE t1/2) was analysed using a mixed model fitting treatment, visit, treatment*visit, baseline gastric emptying t1/2 as fixed effects, and subject as a random effect. The difference between camicinal 50 and placebo for Day 1 and Day 8 was estimated from the model. MDS-UPDRS: The change from baseline in each part of the MDS-UPDRS and total score at the pre-l-dopa dose time point was analysed using a mixed model fitting treatment, visit, treatment*visit, baseline score as fixed effects, and subject as a random effect. The difference between camicinal 50 and placebo for Day 1 and Day 8 was estimated from the model. The change from baseline in MDS-UPDRS part 3 was also derived for at each post-dose time point and analysed using a mixed model fitting treatment, visit, time point and the interaction as fixed effects, time point as repeated effect and subject as a random effect. The baseline measurement of MDS-UPDRS-3 score was included as a covariate in the model. The difference between camicinal 50 and placebo for each time point on Day 1 and Day 8 was estimated from the model. Amount of awake time (in hours) spent ON ON with troublesome dyskinesias, and OFF : The amount of awake hours spent in each state was averaged over a period of 48 hours during the screening period (to be used as baseline) and over days 6-7 of treatment (the treatment period). The change from baseline in the amount of hours spent in each state was analysed using an ANOCVA model, with treatment as a main effect and the baseline amount of hours as a covariate. The difference between camicinal 50 and placebo at the treatment period was estimated from the model. Finger tapping: The change from baseline in finger tap assessment was analysed by a mixed model fitting treatment, visit, time point and the interaction as fixed effects, time point as repeated effect and subject as a random effect. The baseline measurement of finger tap was included as a covariate in the model. The difference between camicinal 50 and placebo for each time point on Day 1 and Day 8 was estimated from the model. L-DOPA dose level and/or dosing frequency changes: The total daily L-DOPA equivalent dose was summarised by study day and treatment. Vital signs, ECG, clinical laboratory data and adverse events: All safety parameters were summarised descriptively. Camicinal PK: Individual camicinal concentration-time profiles for Day 1 and Day 8 were plotted and the concentrations were summarised by visit and time point. PK parameters were calculated from these concentration-time profiles using noncompartmental methods and summarised by visit. Study Population: Male or female subjects, aged 40-80 years old, with advanced Parkinson disease taking L- DOPA with suboptimal motor control. Patients had to be receiving a stable dose of L-DOPA for at least 4 weeks prior to the screening visit and had to have a gastric emptying t ½ time of 70 mins as determined by the 13C-oral breath test. Patients with late stage advanced disease with incapacitating peak dose or biphasic dyskinesia on a stable L- DOPA regime and patients taking medications potentially influencing upper gastrointestinal motility or appetite within one week of the study (e.g., prokinetic drugs, macrolide antibiotics (erythromycin), GLP-1 mimetics) were excluded from the study. Number of Subjects: 040 Total 2
50, 125 Planned, N 15 30 45 Randomised, N 20 38 58 Dosed, N (in All Subjects population) 19 38 57 Completed, n (% ) 18 (95) 37 (97) 55 (96) Total Number Subjects Withdrawn, N (%) 1 (5) 1 (3) 2(4) Withdrawn due to Adverse Events n (%) 0 0 0 Withdrawn due to Lack of Efficacy n (%) 0 0 0 Withdrawn for other reasons n (%) 1 (5) 1 (3) 2(4) Demographics Age (Years) Mean 66.7 (8.04) 67.4 (7.97) 67.1 (7.93) Sex, n (%) Females: 11 (58) 9 (24) 20 (35) Males: 8 (42) 29 (76) 37 (65) BMI (Kg/m 2 ), Mean 26.29 (4.256) 25.97 (3.434) 26.08 (3.693) Height (cm), Mean 168.4 (6.69) 173.5 (6.75) 171.8 (7.11) Weight (Kg), Mean 74.49 (12.466) 78.22 (11.118) 76.98 (11.608) Ethnicity, n (%) Hispanic or Latino: 0 0 0 Not Hispanic or Latino: 19 (100) 38 (100) 57 (100) White, n (%) 19 (100) 38 (100) 57 (100) Primary Efficacy Results: L-DOPA PK Parameter (units) AUC (0-0.5h) (ng.h/ml/) AUC (0-1h) (ng.h/ml/) AUC (0-1.5h) (ng.h/ml/) AUC (0-2h) (ng.h/ml/) Baseline Day 1 Day 8 n 17 35 18 35 17 35 Geometric Mean (SD logs) 0.48 (1.816) 0.72 (1.255) 0.69 (1.483) 0.80 (1.361) 0.55 (0.820) 0.57 (1.443) 0.986 (0.464, 2.095) 0.870 (0.404, 1.874) n 17 35 18 34 17 35 Geometric Mean (SD logs) 2.66 (1.321) 2.62 (1.186) 3.14 (1.143) 3.56 (0.951) 2.91 (0.814) 2.96 (0.881) 1.102 (0.653, 1.861) 1.013 (0.594, 1.727) n 17 35 18 34 17 34 Geometric Mean (SD logs) 5.79 (1.094) 5.72 (0.918) 7.73 (0.672) 7.55 (0.662) 6.58 (0.770) 6.57 (0.635) 0.963 (0.678, 1.369) 1.013 (0.707, 1.452) n 17 34 18 34 17 34 Geometric Mean (SD logs) 9.41 (0.906) 9.34 (0.707) 12.60 (0.501) 11.81 (0.510) 10.83 (0.698) 10.89 (0.489) 0.920 (0.697, 1.214) 1.000 (0.753, 1.328) AUC (0-2.5h) n 17 33 18 32 17 33 3
(ng.h/ml/) Geometric Mean (SD logs) 13.49 (0.690) 13.46 (0.526) 16.87 (0.416) 16.15 (0.407) 15.24 (0..607) 15.07 (0.416) 0.933 (0.739, 1.176) 0.956 (0.754, 1.211) AUC (0-3h) n 17 33 17 31 17 33 (ng.h/ml/) Geometric Mean (SD logs) 17.61 (0.525) 18.04 (0.392) 20.85 (0.379) 20.00 (0.375) 19.53 (0.503) 18.86 (0.379) 0.977 (0.799, 1.195) 0.904 (0.740, 1.105) AUC (0-3.5h) n 17 33 17 31 17 32 (ng.h/ml/) Geometric Mean (SD logs) 21.23 (0.423) 21.92 (0.354) 24.02 (0.366) 23.22 (0.364) 23.10 (0.438) 22.36 (0.358) 0.965 (0.813, 1.144) 0.881 (0.742, 1.045) AUC (0-4h) n 17 33 17 31 17 32 (ng.h/ml/) Geometric Mean (SD logs) 24.13 (0.363) 24.81 (0.350) 26.43 (0.365) 25.66 (0.366) 25.86 (0.406) 25.09 (0.350) 0.965 (0.831, 1.120) 0.886 (0.763, 1.029) Cmax n 17 35 18 35 17 35 (ng/ml/) Geometric Mean (SD logs) 12.77 (0.275) 12.89 (0.408) 13.03 (0.317) 11.64 (0.463) 11.34 (0.364) 11.85 (0.405) 0.864 (0.702, 1.064) 1.018 (0.824, 1.257) Tmax (h) n 17 35 18 35 17 35 Median (range) 1.50 2.00 1.61 1.50 2.00 1.55 (0.3- (0.3, (0.5-3.4) (0.3, 3.5) (0.5, 3.5) (0.3, 4.0) 3.6) 4.0) Median change from baseline (range) 0.00 (- 2.3, 1.3) -0.48 (- 3.5, 1.0) 0.47 (- 1.6, 1.8) 0.00 (- 2.8, 2.9) P-value 0.157 0.186 T1/2 N/A Secondary Outcome Results: Half Gastric Emptying Time (t1/2) (mins) Baseline Day 1 Day 8 0 0 40 50 40 50 n 19 37 19 37 17 36 Mean 99.6 (21.26) 96.9 (21.67) 97.5 (15.81) 91.9 (21.47) 98.7 (25.03) 90.6 (26.75) -2.1 (25.37) -5.0 (17.76) -0.4 (25.90) -4.4 (26.17) Adjusted Means Change -4.239 (-16.015, 7.537) -5.327 (-17.567, 6.914) Pre-L-DOPA Dose MDS-UPDRS 4
MDS-UPDRS Part Baseline Day 1 Day 8 0 40 50 Part 1 n 19 37 19 37 18 36 Mean 9.1 (4.56) 10.1 (6.17) 10.1 (4.98) 8.6 (5.12) 10.0 (5.25) 7.1 (4.67) Baseline 1.0 (2.98) -1.5 (2.93) 1.1 (4.65) -3.0 (3.87) Adjusted -2.16 (-3.90, -0.41) -3.63 (-5.41, -1.85) Part 2 n 19 37 19 37 18 36 Mean 14.9 (7.09) 12.5 (6.33) 16.1 (9.09) 11.5 (6.54) 15.3 (9.29) 10.3 (6.37) Baseline 1.2 (4.16) -1.0 (3.00) 0.6 (5.04) -1.7 (4.60) Adjusted -2.29 (-4.65, 0.07) -2.46 (-4.85, -0.07) Part 3 n 19 37 19 37 18 36 Mean 42.2 (14.63) 38.0 (18.95) 40.4 (17.56) 34.9 (17.97) 44.2 (19.25) 34.0 (17.46) Baseline -1.8 (6.33) -3.1 (8.96) 1.5 (8.64) -3.9 (9.11) Adjusted -1.70 (-6.53, 3.13) -5.38 (-10.28, -0.49) Part 4 n 19 37 19 37 18 36 Mean 5.5 (2.70) 5.3 (3.63) 5.9 (3.07) 5.2 (3.61) 5.7 (3.79) 4.5 (3.41) Baseline 0.4 (1.84) -0.1 (1.98) 0.2 (2.71) -0.7 (1.66) Adjusted -0.56 (-1.65, 0.54) -0.90 (-2.02, 0.22) Total Score n 19 37 19 37 18 36 Mean 71.7 (23.53) 65.8 (27.02) 72.5 (29.01) 60.2 (25.90) 75.2 (34.27) 55.9 (25.34) Baseline 0.8 (10.20) -5.7 (10.34) 3.3 (18.32) -9.2 (12.13) Adjusted -6.69 (-13.77, 0.39) -12.5 (-19.67, -5.29) MDS-UPDRS Part 3 Time point Baseline Day 1 Day 8 0 40 50 120 mins n 19 37 19 37 18 36 Mean 33.1 27.7 32.3 26.2 32.3 (16.61) (16.04) (15.01) (16.25) (14.90) 24.2 (14.24) 5
-0.8 (6.81) -1.5 (7.03) -0.9 (10.49) -2.8 (8.42) -3.18 (-9.11, 2.75) -3.97 (-9.96, 2.03) 180 mins n 19 36 19 37 18 36 Mean 30.3 (14.55) 27.5 (14.21) 31.0 (17.10) 25.5 (18.04) 33.3 (16.17) 25.1 (14.27) 0.7 (10.41) -1.5 (10.22) 3.1 (9.76) -1.2 (8.55) -3.66 (-9.59, 2.27) -5.29 (-11.29, 0.71) 240 mins n 19 37 19 37 18 36 Mean 31.6 (16.27) 29.2 (16.62) 32.7 (20.50) 27.2 (17.68) 37.1 (20.19) 25.4 (15.27) 1.1 (12.36) -1.9 (8.77) 5.1 (11.58) -2.8 (8.16) -4.15 (-10.07, 1.76) -8.90 (-14.88, -2.91) ON/OFF symptoms Amount of hours spent ON Amount of hours spent OFF Baseline (Day -2 and -1) Treatment (Day 6 and 7) 040 50 040 50 n 18 37 18 36 Mean 11.21 (3.602) 11.31 (3.021) 10.61 (3.927) 12.44 (3.375) -0.75 (2.922) 1.03 (2.786) 1.88 (0.28, 3.48) n 18 37 18 36 Mean 4.92 (3.417) 4.23 (2.484) 5.57 (4.364) 2.94 (2.954) 0.93 (2.629) -1.29 (2.236) -2.31 (-3.71, -0.90) Finger Tapping (taps per min) Pre-L- DOPA Dose Baseline Day 1 Day 8 0 40 50 n 19 37 19 36 18 35 Mean 92.4 77.8 92.3 85.1 95.7 92.8 (47.53) (38.00) (43.44) (40.05) (40.90) (43.92) -0.1 (11.65) 7.3 (15.23) 3.1 (14.50) 13.5 (17.65) 6
-2.83 (-21.79, 16.13) 0.51 (-18.51, 19.52) 0 min n 19 35 19 36 18 35 Mean 91.2 (49.84) 80.1 (35.28) 90.7 (40.78) 86.8 (44.65) 92.0 (44.30) 91.1 (42.90) -0.5 (20.04) 8.3 (16.97) 0.3 (21.31) 11.6 (13.96) 0.58 (-18.39, 19.56) 3.32 (-15.70, 22.33) 30 min n 19 34 18 35 18 34 Mean 89.3 (42.91) 85.2 (41.45) 93.4 (43.95) 92.4 (49.92) 95.8 (45.07) 92.2 (41.14) 3.2 (12.61) 8.3 (10.98) 6.3 (16.90) 6.1 (10.27) 1.84 (-17.18, 20.86) -2.94 (-21.97, 16.08) 60 min n 19 36 18 35 18 35 Mean 88.6 (42.32) 89.3 (45.32) 93.8 (44.80) 94.6 (44.06) 94.6 (46.80) 93.2 (39.01) 4.9 (12.66) 3.5 (19.00) 5.5 (11.63) 0.8 (21.75) 0.28 (-18.72, 19.28) -3.12 (-22.13, 15.88) 90 min n 19 36 19 34 18 34 Mean 91.2 (44.14) 90.8 (45.18) 97.7 (50.46) 91.4 (42.09) 95.0 (48.82) 95.5 (42.60) 6.6 (16.72) 2.9 (18.37) 3.3 (14.43) 1.7 (21.46) -3.38 (-22.35, 15.58) -1.38 (-20.40, 17.63) 120 min n 19 37 19 35 18 35 Mean 92.6 (40.99) 92.0 (43.37) 99.9 (50.51) 96.4 (42.06) 97.2 (47.67) 97.4 (42.34) 7.3 (17.46) 3.5 (15.67) 4.3 (13.30) 3.5 (14.45) -4.18 (-23.13, 14.76) -0.71 (-19.70, 18.28) 180 min n 19 37 18 36 18 34 Mean 94.1 (47.19) 92.8 (44.86) 99.0 (49.44) 92.3 (41.01) 96.8 (52.50) 101.2 (49.86) 4.9 (15.90) -0.5 (15.82) 2.6 (13.07) 6.0 (21.73) -6.39 (-25.36, 12.58) 3.02 (-15.98, 22.02) 240 min n 19 37 18 36 18 35 Mean 95.2 (44.60) 93.2 (46.17) 98.2 (51.97) 97.6 (48.40) 98.3 (53.30) 102.8 (51.84) 2.1 (16.68) 4.3 (15.19) 2.6 (16.42) 7.7 (23.12) 7
0.77 (-18.20, 19.75) 4.08 (-14.91, 23.07) Total daily L-DOPA equivalent dose () Study Day Baseline n 19 37 Mean 113.2 (41.14) 164.5 (119.66) Day 1 n 19 37 Mean 353.9 (174.85) 368.6 (216.54) Day 2 n 19 36 Mean 465.8 (229.61) 514.5 (300.44) Day 3 n 19 36 Mean 481.6 (243.79) 516.9 (299.98) Day 4 n 19 36 Mean 481.6 (241.50) 518.3 (313.07) Day 5 n 19 36 Mean 484.2 (243.13) 503.0 (293.48) Day 6 n 17 36 Mean 516.2 (249.21) 511.3 (307.31) Day 7 n 17 35 Mean 486.8 (247.51) 499.6 (310.57) Day 8 n 17 34 Mean 191.2 (175.43) 281.3 (234.00) 040 PK PK Parameter (Units) Day 1 Day 8 AUC(0-5.5) n 36 36 (ng.h/ml) Geometric Mean (SD logs) 1632.5 (0.368) 3036.9 (0.437) Cmax (ng/ml) n 36 36 Geometric Mean (SD logs) 501.0 (0.433) 788.3 (0.438) Tmax (h) n 36 36 Mean 1.312 (0.9660) 1.393 (0.9863) Safety Results: An on therapy adverse event (AE) was defined as an AE with onset on or after the start date of study medication., 125 (N=38) Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with any AE(s), n(%) 17 (89%) 24 (63%) Headache 7 (37%) 9 (24%) Fatigue 2 (11%) 5 (13%) Nausea 4 (21%) 3 (8%) Constipation 3 (16%) 2 (5%) Dizziness 4 (21%) 1 (3%) Abdominal pain upper 2 (11%) 2 (5%) Back pain 1 (5%) 3 (8%) Diarrhoea 2 (11%) 1 (3%) Muscle spasms 3 (16%) 0 8
Toothache 2 (11%) 1 (3%) Anaemia 2 (11%) 0 Arthralgia 2 (11%) 0 Dyskinesia 0 2 (5%) Parkinson's disease 2 (11%) 0 Pruritus 0 2 (5%) Somnolence 0 2 (5%) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication], 125 (N=38) Subjects with non-fatal SAEs, n (%) 2 (11%) 2 (5%) n (%) [related] n (%) [related] 1 (5%) [0] 0 Ankle fracture Rib fracture 1 (5%) [0] 0 Parkinson's disease 1 (5%) [1] 0 Pruritus 0 1 (3%) [0] Circulatory collapse 0 1 (3%) [0] Subjects with fatal SAEs, n (%) 0 0 Conclusion: There were no significant differences in the L-DOPA exposure (as assessed by AUC) after the initial dose or after 8 days dosing of placebo or camicinal 50. Nonetheless, the group receiving camicinal had statistically and clinically meaningful less OFF time and more ON time than those receiving placebo. In addition, there was a statistically and clinically meaningful improvement in symptoms related to motor dysfunction in subjects receiving camicinal verses those receiving placebo. This improvement in OFF time may be related to an associated decrease (30-60 minutes) in the time to maximal L-DOPA plasma concentration (Tmax) observed in this study. There was a moderate, nonsignificant improvement in half gastric emptying time compared to placebo. No differences were observed between camicinal and placebo in the number of finger taps per minute or in the L-DOPA dosage. In the camicinal treatment group, a total of 24 (63%) subjects reported non-serious adverse events, with the most frequent events being headache, fatigue, back pain and nausea. In the placebo treatment group, 17 (89%) subjects reported non-serious adverse events, with the most frequent being headache, nausea and dizziness. Non-fatal serious adverse events of pruritus and circulatory collapse were reported in the camicinal treatment group and rib fracture, ankle fracture and Parkinson s disease (worsening) in the placebo treatment group. There were no fatalities reported in this study. 9