L-DOPA III ( ( [ ] UPDRS Part III Observed Case(OC UPDRS Part III 4.05 OC Last Observation Carried Forward(LOCF S.D

Transcription

1 (3 III L-DOPA 6, 7 1 III L-DOPA ( L-DOPA L-DOPA III L-DOPA III ( L-DOPA 3 L-DOPA ( Modified Hoehn & Yahr (2L-DOPA 1Wearing-off 2on-off 3 L-DOPA 4L-DOPA 5L-DOPA 6 (1 4 (2 (3 (4 (5 100 mmhg (6 (7 (8 (9 (10 (11 6 (12 (

2 L-DOPA III ( ( [ ] UPDRS Part III Observed Case(OC UPDRS Part III 4.05 OC Last Observation Carried Forward(LOCF S.D UPDRS Part III 50% 2.0 S.D.12 LOCF ITT UPDRS Part II % mg 0.5 mg 2.5 mg ( mg2 / 1.25 mg fixed flexible 4.5 mg/ 22.5 mg/ mg/0.25 a 0.5 a 1.0 a c 2.5 d 3.0 e 3.5 c 4.5 f mg/1.25 b 2.5 b 5.0 a a1 2 b c 0.5 mg d 0.5 mg e 0.5 mg f 0.5 mg ( ( mg/ a 0.5 b a1 2 b1 1 mg/ a 2.5 b (1 1 2 lisuride (2 1 L-DOPA DCI L-DOPA

3 L-DOPA III ( ( b (4 Modified Hoehn & Yahr UPDRS a ( ( ( c c c aunified Parkinson s Disease Rating Scaleb12 c ( 1 UPDRS Part II on off UPDRS Part III on UPDRS Part II AUC 12 2 UPDRS Part III AUC 12 3 UPDRS Part II 4 UPDRS Part III 5 UPDRS Part I UPDRS Part IV UPDRS Part IIII 8 UPDRS Part IIV 9 Modified Hoehn & Yahr I II III IV V 11 UPDRS Responder UPDRS Part IIon off Part III 5% Wilcoxon 50 90% UPDRS Part II 1.0UPDRS Part III 2.0 Wilcoxon Fisher LOCFLast Observation Carried Forward UPDRS Fisher Wicoxon Wilcoxon ,

4 L-DOPA 3 L-DOPA ( mg/ 22.5 mg/ UPDRS L-DOPA III 7,8,9 UPDRS II mg2 / 1.5 mg3 / L-DOPA III mg3 / 1.5 mg3 / mg2 / 1.5 mg3 / 4.5 mg/ 1.25 mg1 / 7.5 mg3 / 22.5 mg/ mg2 / III

5 a 325 PPX BROM PPX 102 BROM PPX 13 BROM PPX 89 BROM PPX BROM 102 ( ( ( ( ( ( ( ( ( ( ( ( (0.0 0 (0.0 1 (0.9 1 (0.3 8 ( ( ( (8.9 2 (2.0 0 (0.0 0 (0.0 2 (0.6 3 (2.9 3 (2.9 5 ( (3.5 0 (0.0 1 (1.0 1 (0.9 2 (0.6 PPX BROM ( % (TABLE 10.1:2 i % PPX ( [ ], [ ], [ ] PPX ( [ ], [ ], [ ] 4 ( [ ], [ ], [ ] PPX ( [ ], [ ], [ ] PPX ( [ ], [ ], [ ] PPX 100mmHg 115mmHg BROM 90mmHg 124mmHg 90mmHg 125mmHg 100mmHg PPX 96mmHg 112mmHg BROM 93mmHg 106mmHg PPX BROM (TABLE :2-126

6 PPX BROM (315 (102 (105 (108 A C C3 D1 D2 E1 E2 F1 F2 F3 Z1 Z2 [ ] % 125% UPDRS UPDRS ( ( ( (202 PPX BROM (TABLE :1 ii FAS PP 91 FAS PP ( intent-to-treat (Full analysis dataset; FAS UPDRS UPDRS Part II UPDRS Part III UPDRS Part II off (off ( (Per protocol dataset; PP -127

7 PP ( % L-DOPA DCI L-DOPA 100 mg/ UPDRS Part III off 10 9 UPDRS Part III off UPDRS Part III FAS FAS PP 9 91 a FAS PP 45.4% BROM 49.5% a C3 PPX 40.0% BROM 48.1% PPX 15 D1 BROM, PPX L-DOPA D2 150 mg/ 300 mg/ L-DOPA SE 600 mg/ 750mg/ F3 UPDRS Part III off FAS PP PPX BROM (TABLE :2 315 PPX 102 BROM FAS 313 PP 300 LOCFLast Observation Carried Forward -128

8 PPX 105 BROM PPX 102 PPX 3 BROM 105 BROM FAS 313 FAS 2 PPX 102 PPX 0 BROM 104 BROM PP 300 PP 13 PPX 98 PPX 4 BROM 101 BROM PPX BROM 6 (FIGURE 10.1: 111.1: 1 b FAS 313 PPX 102 BROM

9 PPX BROM (102 (104 (107 (313 p 60 ( ( ( ( ( ( ( ( b 35 2 (2.0 0 (0.0 1 (0.9 3 ( c (1.0 0 (0.0 3 (2.8 4 ( (8.8 8 ( ( ( ( ( ( ( ( ( ( ( ( (9.6 8 ( (9.9 S.D ( ( ( ( c ( ( ( (36.1 (cm (8.8 4 (3.8 9 ( ( (0.0 2 (1.9 0 (0.0 2 (0.6 S.D ( ( ( ( c ( ( ( ( ( ( ( (19.8 kg (8.8 5 ( ( ( (2.0 2 (1.9 1 (0.9 5 (1.6 S.D ( ( ( ( c ( ( ( ( (4.9 3 ( ( ( (2.0 3 (2.9 4 (3.7 9 ( (6.9 8 (7.7 9 ( ( c ( ( ( ( ( ( ( (40.6 (Modified (2.9 2 (1.9 6 ( (3.5 Hoehn & 5 1 (1.0 0 (0.0 2 (1.9 3 (1.0 Yahr c UPDRS Part II a S.D c UPDRS Part III S.D a on off b 2 c Kruskal-Wallis ( % PPX BROM (TABLE :1-130

10 ( PPX BROM (102 (104 (107 (313 p 300mg 56 ( ( ( ( c mg 34 ( ( ( ( mg 10 (9.8 6 (5.8 5 ( (6.7 L-DOPA mg 1 (1.0 0 (0.0 0 (0.0 1 ( mg 1 (1.0 4 (3.8 5 ( (3.2 S.D ( ( ( ( b 72 ( ( ( ( ( (9.6 7 ( ( ( ( ( ( ( ( ( ( (9.8 9 ( ( ( ( ( ( ( b 29 ( ( ( (26.5 a on off b 2 c Kruskal-Wallis ( % PPX BROM (TABLE :1 c FAS PPX BROM mg/ S.D mg/ PPX 1.5 mg/ 90%82/91 BROM 7.5 mg/ 95%87/91 PPX BROM 4.5mg/ 22.5 mg/ % % 93 PPX 102 BROM 104 % b % b mg/ mg/ ( ( ( ( ( ( ( ( a a S.D mg/ S.D mg/ a 812 b ( (TABLE 11.4:1 PPX BROM -131

11 d i UPDRS Part II PPX FAS UPDRS Part II on off 94 PPX PPX PPX p0.001 UPDRS Part II PP PPX 95 94FAS PPX UPDRS Part II 25% 75% Wilcoxon ( PPX 102 ( ( ( p ( ( ( PPX (TABLE :1 95PP PPX UPDRS Part II 25% 75% Wilcoxon ( PPX 98 ( ( ( p ( ( ( PPX (TABLE :1 PPX BROM FAS UPDRS Part II 96 UPDRS Part II PPX BROM PPX BROM % UPDRS Part II 1.0 PP PPX BROM

12 FAS PPX BROM UPDRS Part II S.D. (90% ( PPX BROM ( PPX BROM (TABLE : 1 97PP PPX BROM UPDRS Part II S.D. (90% ( PPX BROM ( PPX BROM (TABLE :1 ii UPDRS Part III PPX FAS UPDRS Part III 98 PPX PPX PPX p0.001 UPDRS Part III PP PPX 99 98FAS PPX UPDRS Part III 25% 75% Wilcoxon ( PPX 102 ( ( ( p ( ( ( PPX (TABLE :1 99PP PPX UPDRS Part III 25% 75% Wilcoxon ( PPX 98 ( ( ( p ( ( ( PPX (TABLE :1-133

13 PPX BROM FAS UPDRS Part III 100 UPDRS Part III PPX BROM PPX BROM % UPDRS Part III 2.0 PP PPX BROM FAS PPX BROM UPDRS Part III S.D. (90% ( PPX BROM ( PPX BROM (TABLE :1 101PP PPX BROM UPDRS Part III S.D. (90% ( PPX BROM ( PPX BROM (TABLE :1 iii UPDRS Part II Part III PPX BROM UPDRS Part II PPX PPX BROM PPX BROM -134

14 (FIGURE : : 1 PPX BROM Wilcoxon vs a p vs BROM a PPX (TABLE : : 1 PPX BROM 7UPDRS Part II PPX BROM UPDRS Part III PPX PPX BROM PPX PPX BROM PPX 102 BROM (FIGURE : : 2 PPX BROM Wilcoxon vs p vs BROM PPX BROM (TABLE : : 2 8UPDRS Part III -135

15 iv UPDRS Part II AUC Part III AUC UPDRS Part II Part III 212 AUC 102 PPX UPDRS Part II Part III AUC p0.001ppx BROM AUC UPDRS Part II Part III 102UPDRS Part IIAUC Part III AUC PPX BROM Wilcoxon UPDRS Part II PPX vs p0.001 AUC 25% PPX vs BROM p= % UPDRS Part III PPX vs p0.001 AUC 25% PPX vs BROM p= % PPX BROM (TABLE 14.2:5, 14.2:6 v UPDRS Part IIIIPart IIV UPDRS Part IIII Part IIV 103 PPX UPDRS Part IIII Part IIV p0.001ppx BROM 103UPDRS Part IIIIPart IIV PPX BROM Wilcoxon UPDRS Part IIII PPX vs p % PPX vs BROM p= % UPDRS Part IIV PPX vs p % PPX vs BROM p= % PPX BROM (TABLE 14.2:5, 14.2:6 vi UPDRS Part IPart IV UPDRS Part I Part IV 104 UPDRS Part I PPX BROM UPDRS Part I ( 1033% -136

16 L-DOPA (Confusion13.8% 51 40% D 52 ( UPDRS Part I PPX 14 UPDRS Part I UPDRS Part I UPDRS Part IV PPX p=0.006 PPX BROM 104UPDRS Part I Part IV PPX 102 BROM Fisher 26 ( ( (15.0 UPDRS Part I PPX vs p= ( ( (79.4 PPX vs BROM p= (4.9 9 (8.7 6 ( ( ( (15.9 UPDRS Part IV PPX vs p= ( ( (71.0 PPX vs BROM p= ( ( (13.1 PPX BROM ( % (TABLE 14.2:11, TABLE 14.2:12 vii Modified Hoehn & Yahr Modified Hoehn & Yahr 105 PPX Modified Hoehn & Yahr BROM p0.001brom p= QA, 58:126, 20, (

17 Modified Hoehn & Yahr PPX 102 BROM Fisher 61 ( ( (30.8 Modified Hoehn PPX vs p ( ( (66.4 & Yahr PPX vs BROM p= (1.0 2 (1.9 3 (2.8 PPX BROM ( % (TABLE 14.2:11, 14.2:12 viii UPDRS Part II Part III UPDRS Part II PPX PPX BROM -138

18 UPDRS Part II PPX BROM p Fisher (107 PPX vs PPX vs BROM 28 ( ( ( ( ( ( (2.9 4 (3.8 2 ( ( ( ( ( ( ( (3.9 2 (1.9 1 ( ( ( ( ( ( ( (1.0 2 (1.9 1 ( ( ( ( ( ( ( (1.0 4 (3.8 2 ( ( ( ( ( ( ( (1.0 5 (4.8 5 ( ( ( ( ( ( ( (1.0 3 (2.9 3 ( ( ( ( ( ( ( (2.0 2 (1.9 5 ( ( ( ( ( ( ( (1.0 2 (1.9 8 ( ( ( ( ( ( ( (2.0 4 (3.8 3 ( ( ( ( ( ( ( (2.9 9 (8.7 7 ( ( ( ( ( ( ( (2.0 3 (2.9 5 ( ( ( ( ( ( ( (1.0 4 (3.8 2 (1.9 9 ( ( ( ( ( ( (3.9 4 (3.8 1 (0.9 PPX BROM ( % (TABLE 14.2:7, 14.2:8-139

19 UPDRS Part III PPX PPX BROM 107UPDRS Part III PPX BROM p Fisher (107 PPX vs PPX vs BROM 26 ( ( ( ( ( ( (2.0 3 (2.9 2 ( ( ( ( ( ( ( (0.0 1 (1.0 3 ( ( ( ( ( ( ( (0.0 5 (4.8 1 ( ( ( ( ( ( ( (2.9 5 (4.8 4 ( ( ( ( ( ( ( (2.9 7 (6.7 9 ( ( ( ( ( ( ( (2.0 7 (6.7 9 ( ( ( ( ( ( ( (3.9 4 (3.8 8 ( ( ( ( ( ( ( (4.9 8 ( ( ( ( ( ( ( ( (3.9 5 (4.8 4 ( ( ( ( ( ( ( (3.9 4 (3.8 5 ( ( ( ( ( ( ( (2.9 1 (1.0 7 ( ( ( ( ( ( ( (3.9 1 (1.0 6 ( ( ( ( ( ( ( (3.9 3 (2.9 2 ( ( ( ( ( ( ( (2.0 4 (3.8 3 (2.8 PPX BROM ( % (TABLE 14.2:9, 14.2:10-140

20 ix UPDRS Part II Part III PPX 108 UPDRS Part II UPDRS Part III PPX L-DOPA 1 600mg UPDRS Part II Part III 95% 0 PPX % 108PPX UPDRS Part II Part III UPDRS Part II UPDRS Part III a a PPX 95% 95% cm kg L-DOPA (mg PPX a PPX (TABLE 14.2:14 PPX BROM 109 UPDRS Part IIUPDRS Part III kg PPX % 0 PPX BROM -141

21 PPX BROM UPDRS Part II Part III UPDRS Part II UPDRS Part III a a PPX BROM 95% 95% cm kg L-DOPA (mg PPX BROM abrom PPX (TABLE 14.2:15 x 110 PPX 61.8%63/ %30/107 BROM 47.1%49/104 PPX BROM p0.001 p= a Wilcoxon PPX vs PPX vs BROM PPX (10.8 (51.0 (19.6 (14.7 (0.0 (3.9 (100 ( BROM p0.001 p=0.022 (9.6 (37.5 (26.0 (23.1 (2.9 (1.0 (100 ( (2.8 (25.2 (28.0 (42.1 (0.9 (0.9 (100 (28.0 PPX BROM ( % a (TABLE :1, :1-142

22 xi UPDRS Responder UPDRS Part IIPart III IIV UPDRS Part II 30% PPX BROM 56.9%49.0%29.9%UPDRS Part III 63.7%60.6% 36.4%UPDRS Part IIV 61.8%51.9%36.4% UPDRS Part IIPart III Part IIV PPX Responder (p 0.001PPX BROM 111UPDRS Part IIPart III Part IIV % -30% Fisher < < < 10 10< (95% PPX vs PPXvsBROM PPX (44.1 (12.7 (17.6 (24.5 (1.0 (100 ( UPDRS BROM Part II (32.7 (16.3 (16.3 (27.9 (6.7 (100 ( (19.6 (10.3 (22.4 (39.3 (8.4 (100 ( PPX (47.1 (16.7 (16.7 (17.6 (2.0 (100 ( UPDRS BROM Part III (40.4 (20.2 (14.4 (18.3 (6.7 (100 ( (18.7 (17.8 (18.7 (38.3 (6.5 (100 ( PPX (40.2 (21.6 (17.6 (18.6 (2.0 (100 ( UPDRS BROM Part IIV (35.6 (16.3 (22.1 (17.3 (8.7 (100 ( (19.6 (16.8 (17.8 (39.3 (6.5 (100 ( PPX BROM ( % (TABLE 14.2:13 e i PPX 102 BROM S.D. PPX BROM S.D. PPX mg/ mg/ 93 BROM mg/ mg/

23 ii 2% WHO ART 112 PPX 85.3%87/102 BROM 90.5%95/ % 83/108 PPX BROM (vs p=0.159vs BROM p= % PPX 15.7% 13.7% BROM 30.5% 24.8% 15.2% PPX 17.6% 14.7% BROM 30.5%24.8% 10% PPX BROM 10% ( PPX BROM 5 4.9%4.8% PPX BROM PPX 69.6%71/102 BROM 72.4%76/ % 59/108 PPX p=0.033brom (p= % PPX 23.5% 18.6% 16.7% 15.7% 12.7% 11.8% 10.8% BROM 24.8%23.8%19.0% 15.2% 14.3% 14.3% 10.5% 10% BROM PPX PPX 16/102 (15.7% BROM 9/105 (8.6% L-DOPA III ( PPX 32/80 (40.0% BROM 38/84 (45.2% L-DOPA L-DOPA 45% off 3.04 on L-DOPA L-DOPA 27% 10% on 53 Boas J. et al. European Journal of Neurology 3, (

24 % PPX BROM a (% a 12 ( ( ( ( ( (12.0 (Hypotension orthostatic 4 (3.9 5 (4.9 5 (4.8 5 (4.8 0 (0.0 0 (0.0 (Mouth dry 10 ( ( ( ( ( ( ( ( ( ( ( (23.1 (Chest pain 0 (0.0 2 (2.0 2 (1.9 5 (4.8 1 (0.9 3 (2.8 (Fall 0 (0.0 5 (4.9 0 (0.0 1 (1.0 0 (0.0 3 (2.8 (Influenza-like symptom 0 ( ( ( ( (0.0 9 (8.3 (Oedema peripheral 0 (0.0 1 (1.0 2 (1.9 3 (2.9 2 (1.9 3 (2.8 (Pain 0 (0.0 1 (1.0 0 (0.0 3 (2.9 0 (0.0 5 ( ( ( ( ( ( (35.2 (Dizziness 11 ( ( ( ( ( (13.0 (Dyskinesia 16 ( ( (7.6 9 (8.6 6 (5.6 6 (5.6 (Dystonia 3 (2.9 4 (3.9 0 (0.0 0 (0.0 1 (0.9 1 (0.9 (Headache 6 ( ( ( ( ( (9.3 (Hypoaesthesia 0 (0.0 0 (0.0 1 (1.0 3 (2.9 3 (2.8 4 (3.7 (Somnolence 12 ( ( ( ( ( ( ( ( ( ( ( (47.2 (Abdominal pain 0 (0.0 2 (2.0 2 (1.9 3 (2.9 3 (2.8 5 (4.6 (Constipation 13 ( ( ( ( ( (12.0 (Diarrhoea 0 (0.0 2 (2.0 0 (0.0 4 (3.8 0 (0.0 3 (2.8 (Dyspepsia 24 ( ( ( ( ( (17.6 (Nausea 19 ( ( ( ( ( (22.2 (Stomatitis 2 (2.0 4 (3.9 0 (0.0 4 (3.8 1 (0.9 1 (0.9 (Vomiting 8 ( ( (6.7 7 (6.7 2 (1.9 3 (2.8 1 (1.0 5 (4.9 2 (1.9 6 (5.7 2 (1.9 8 (7.4 ((Back pain 1 (1.0 5 (4.9 2 (1.9 5 (4.8 1 (0.9 7 ( ( ( ( ( ( (30.6 (Anorexia 17 ( ( ( ( ( (14.8 (Anxiety 1 (1.0 2 (2.0 4 (3.8 9 (8.6 0 (0.0 2 (1.9 (Hallucination 13 ( ( ( ( (3.7 4 (3.7 ( (Insomnia 4 (3.9 6 (5.9 6 ( (9.5 4 ( ( (1.0 5 (4.9 3 (2.9 9 (8.6 3 ( (13.0 (Pruritus 0 (0.0 0 (0.0 0 (0.0 3 (2.9 1 (0.9 2 (1.9 (Sweating increased 0 (0.0 0 (0.0 2 (1.9 3 (2.9 2 (1.9 2 (1.9 0 (0.0 0 (0.0 2 (1.9 4 (3.8 2 (1.9 2 (1.9 (Taste perversion 0 (0.0 0 (0.0 1 (1.0 3 (2.9 1 (0.9 1 (0.9 PPX BROM ( % (TABLE :1 WHO ART

25 WHO ART a 102 b PPX (% (30.4 (29.4 (9.8 (69.6 (85.3 (Autonomic Nervous System Disorders 5 (4.9 6 (5.9 1 ( ( (12.7 (Hypotension Postural 2 (2.0 2 (2.0 4 (3.9 5 (4.9 (Mouth Dry 3 (2.9 6 (5.9 1 ( ( ( ( ( ( ( (51.0 (Central & Peripheral Nervous System Disordres (Delirium 1 (1.0 1 (1.0 1 (1.0 (Dizziness 9 (8.8 2 ( ( (17.6 (Dyskinesia 5 (4.9 7 (6.9 4 ( ( ( (1.0 1 (1.0 1 (1.0 (Muscle Contractions Involuntary (Somnolence 9 (8.8 2 (2.0 1 ( ( (14.7 (Gastro-Intestinal System Disorders 23 ( ( ( ( (52.9 (Constipation 5 (4.9 6 (5.9 2 ( ( (18.6 (Vomiting 3 (2.9 3 (2.9 2 (2.0 8 ( (10.8 (Dyspepsia 15 ( (7.8 1 ( ( (25.5 (Nausea 13 ( (2.9 3 ( ( (23.5 (Stomatitis Aphthous 1 (1.0 1 (1.0 1 (1.0 (Liver And Biliary System Disorders 1 (1.0 1 (1.0 1 (1.0 (Hepatic Function Abnormal 1 (1.0 1 (1.0 1 (1.0 (Psychiatric Disorders 20 ( ( ( ( (35.3 (Agitation 1 (1.0 1 (1.0 1 (1.0 (Anorexia 11 ( ( ( (17.6 (Hallucination 8 (7.8 4 (3.9 1 ( ( (13.7 ( (Insomnia 3 (2.9 1 (1.0 4 (3.9 6 (5.9 (Automatism 1 (1.0 1 (1.0 1 (1.0 a b PPX ( % -146

26 ( WHO ART a BROM 105 b (% (37.1 (27.6 (7.6 (72.4 (90.5 (Autonomic Nervous System Disorders 9 (8.6 6 (5.7 1 ( ( (19.0 (Hypotension Postural 4 (3.8 1 (1.0 5 (4.8 5 (4.8 (Mouth Dry 4 (3.8 5 (4.8 1 ( ( (12.4 (Body As A Whole-General Disorders 3 (2.9 3 (2.9 6 ( (27.6 (Oedema Peripheral 1 (1.0 1 (1.0 2 (1.9 3 (2.9 (Asthenia 1 (1.0 1 (1.0 2 (1.9 2 (1.9 (Chest Pain 1 (1.0 1 (1.0 2 (1.9 5 ( ( ( ( ( (59.0 (Central & Peripheral Nervous System Disordres (Delirium 1 (1.0 1 (1.0 1 (1.0 (Dizziness 22 ( ( ( (30.5 (Dyskinesia 5 (4.8 1 (1.0 2 (1.9 8 (7.6 9 (8.6 (Headache 5 (4.8 3 (2.9 8 ( (15.2 (Hypoaesthesia 1 (1.0 1 (1.0 3 (2.9 (Somnolence 12 ( (5.7 2 ( ( (24.8 (Gastro-Intestinal System Disorders 25 ( ( ( ( (55.2 (Constipation 6 (5.7 4 (3.8 1 ( ( (18.1 (Vomiting 5 (4.8 2 (1.9 7 (6.7 7 (6.7 (Dyspepsia 13 ( (1.9 1 ( ( (21.9 (Nausea 20 ( ( ( (30.5 (Hearing And Vestibular Disorders 1 (1.0 1 (1.0 3 (2.9 (Tinnitus 1 (1.0 1 (1.0 2 (1.9 (Metabolic And Nutritonal Disorders 1 (1.0 1 (1.0 2 (1.9 3 (2.9 (Weight Decrease 1 (1.0 1 (1.0 1 (1.0 (Musculo-Skeletal System Disorders 1 (1.0 1 (1.0 2 (1.9 6 (5.7 ((Back Pain 1 (1.0 1 (1.0 2 (1.9 5 (4.8 (Psychiatric Disorders 23 ( (7.6 2 ( ( (41.0 (Agitation 1 (1.0 1 (1.0 2 (1.9 2 (1.9 (Anorexia 10 (9.5 4 (3.8 1 ( ( (19.0 (Anxiety 3 (2.9 1 (1.0 4 (3.8 9 (8.6 (Delusion 1 (1.0 1 (1.0 1 (1.0 (Hallucination 11 ( (2.9 1 ( ( (15.2 ( (Insomnia 3 (2.9 2 (1.9 1 (1.0 6 ( (9.5 (Skin And Appendages Disorders 1 (1.0 2 (1.9 3 (2.9 9 (8.6 (Rash 1 (1.0 1 (1.0 2 (1.9 (Sweating Increased 1 (1.0 1 (1.0 2 (1.9 3 (2.9 (Special Senses Other, Disorders 1 (1.0 1 (1.0 2 (1.9 4 (3.8 (Parosmia 1 (1.0 1 (1.0 2 (1.9 2 (1.9 a b BROM ( % -147

27 ( WHO ART a 108 b (% (35.2 (16.7 (2.8 (54.6 (76.9 (Autonomic Nervous System Disorders 7 (6.5 2 (1.9 1 ( ( (12.0 (Hypotension 1 (0.9 1 (0.9 1 (0.9 (Mouth Dry 7 (6.5 1 (0.9 1 (0.9 9 ( (11.1 (Body As A Whole-General Disorders 5 (4.6 2 (1.9 7 ( (23.1 (Asthenia 2 (1.9 2 (1.9 2 ( ( (9.3 1 ( ( (35.2 (Central & Peripheral Nervous System Disordres (Dystonia 1 (0.9 1 (0.9 1 (0.9 (Dizziness 7 (6.5 3 ( ( (13.0 (Dyskinesia 3 (2.8 2 (1.9 1 (0.9 6 (5.6 6 (5.6 (Headache 2 (1.9 2 (1.9 4 ( (9.3 (Hypoaesthesia 2 (1.9 1 (0.9 3 (2.8 4 (3.7 (Somnolence 8 (7.4 4 ( ( (13.0 (Parkinsonism Aggravated 1 (0.9 1 (0.9 1 (0.9 (Gastro-Intestinal System Disorders 26 ( (4.6 2 ( ( (47.2 (Constipation 4 (3.7 3 (2.8 1 (0.9 8 ( (12.0 (Vomiting 1 (0.9 1 (0.9 2 (1.9 3 (2.8 (Dyspepsia 13 ( ( ( (17.6 (Flatulence 1 (0.9 1 (0.9 2 (1.9 2 (1.9 (Nausea 14 ( (2.8 1 ( ( (22.2 (Psychiatric Disorders 18 ( ( ( (30.6 (Anorexia 12 ( ( ( (14.8 (Depression 1 (0.9 1 (0.9 1 (0.9 (Skin And Appendages Disorders 2 (1.9 1 (0.9 3 ( (13.0 (Sweating Increased 1 (0.9 1 (0.9 2 (1.9 2 (1.9 a b ( % -148

28 % 114 (PPX 1.5 mg/ BROM 7.5 mg/ PPX BROM 55.9%60.0% PPX 1.5mg/ 3.0mg/ 18.5%3.0mg/ 4.5mg/ 12.2% 1.5mg/ 4.5 mg/ 3.0mg/ % 1 mg <1.5 PPX <7.5 <3.0 <4.5 <15.0 <22.5 BROM (% (Mouth dry 4 (3.9 4 (4.3 1 (1.4 2 ( ( (4.8 3 (3.2 3 (3.8 2 ( ( ( (2.0 4 (4.3 2 (2.7 4 ( ( (2.9 6 (6.3 3 (3.8 3 ( ( (8.3 (Influenza-like symptom (Dizziness 9 (8.8 5 (5.4 2 (2.7 2 ( ( ( (9.5 4 (5.1 3 ( ( (13.0 (Dyskinesia 2 (2.0 8 (8.7 5 (6.8 1 ( ( (0.0 2 (2.1 4 (5.1 3 (4.8 9 (8.6 6 (5.6 (Headache 7 (6.9 4 (4.3 1 (1.4 0 ( ( (7.6 4 (4.2 1 (1.3 3 ( ( (9.3 (Somnolence 8 (7.8 2 (2.2 3 (4.1 2 ( ( ( (6.3 2 (2.6 2 ( ( (13.0 (Constipation 10 (9.8 3 (3.3 4 (5.4 2 ( ( (8.6 5 (5.3 3 (3.8 2 ( ( (12.0 (Dyspepsia 13 ( (7.6 1 (1.4 5 ( ( ( (4.2 2 (2.6 4 ( ( (17.6 (Nausea 13 ( (5.4 3 (4.1 3 ( ( ( (6.3 5 (6.4 1 ( ( (22.2 (Vomiting 6 (5.9 2 (2.2 2 (2.7 1 ( ( (3.8 2 (2.1 0 (0.0 1 (1.6 7 (6.7 3 (2.8 (Anorexia 9 (8.8 4 (4.3 3 (4.1 2 ( ( (7.6 6 (6.3 4 (5.1 2 ( ( (14.8 (Hallucination 6 (5.9 6 (6.5 1 (1.4 1 ( ( (4.8 6 (6.3 3 (3.8 2 ( ( (3.7 ((Insomnia 0 (0.0 4 (4.3 1 (1.4 1 (1.8 6 (5.9 7 (6.7 1 (1.1 1 (1.3 1 ( ( (12.0 ( % (TABLE :3 10% 115 PPX 77.5%7.5%1.1%BROM 82.9%7.7%1.1% 70.4%6.4%1.1% 90.8%91.6%91.6% PPX -149

29 % PPX BROM (% (Mouth dry 9 (8.8 2 (2.2 0 ( ( ( (2.2 0 ( ( (8.3 3 (3.2 0 ( (3.9 8 (8.6 0 ( ( ( (3.3 1 ( ( (5.6 2 (2.1 1 ( (Influenza-like symptom (Dizziness 12 ( (5.4 1 ( ( ( (2.2 1 ( ( (8.3 5 (5.3 0 ( ( (2.2 0 ( ( (6.7 2 (2.2 0 (0.0 9 (8.6 5 (4.6 1 (1.1 0 ( (Dyskinesia (Headache 10 (9.8 2 (2.2 0 ( ( ( (1.1 1 ( ( (7.4 2 (2.1 0 ( (Somnolence 13 ( (2.2 0 ( ( ( (5.5 0 ( ( ( (0.0 0 ( (Constipation 15 ( (4.3 0 ( ( ( (3.3 1 ( ( (8.3 2 (2.1 2 ( (Dyspepsia 22 ( (4.3 0 ( ( ( (6.6 0 ( ( ( (3.2 1 ( (Nausea 18 ( (5.4 1 ( ( ( (3.3 1 ( ( ( (3.2 3 ( (Vomiting 9 (8.8 1 (1.1 1 ( ( (4.8 2 (2.2 0 (0.0 7 (6.7 3 (2.8 0 (0.0 0 ( (Anorexia 17 ( (1.1 0 ( ( ( (4.4 0 ( ( ( (2.1 1 ( (Hallucination 11 ( (2.2 1 ( ( ( (2.2 0 ( ( (2.8 1 (1.1 0 ( ((Insomnia 4 (3.9 2 (2.2 0 (0.0 6 (5.9 6 (5.7 3 (3.3 1 ( (9.5 9 (8.3 3 (3.2 1 ( (TABLE :4 ( % iii PPX 3 BROM 1 116BROM mg/ ( PPX BROM 0 44 ( 6 15 PPX BROM (TABLE 12.3:1 iv 117 PPX 8, BROM 12 9 PPX 4 BROM 7 3 PPX BROM 2 1 PPX BROM 2 BROM -150

30 PPX ( mg/ PPX a ( ( ( BROM a a a PPX BROM ( % (TABLE :5 v 118 PPX 23.8%24/101 BROM 18.3%19/ % 15/107 PPX BROM (vs p=0.078vs BROM p=0.392 PPX 18.8%19/101 BROM 17.3%18/ %13/107 PPX BROM (vs p=0.248vs BROM p=0.857 PPX CK7.1% 6.1% AST(GOT4.0%ALT(GPT -151

31 %BROM CK9.0%LDH3.9% 3.8% 118 PPX BROM a (% (0.0 0 ( (0.0 0 ( (0.0 0 ( (1.0 1 ( (0.0 1 ( (0.9 1 ( (1.0 1 ( (0.0 0 ( (2.8 3 ( (1.0 1 ( (0.0 0 ( (2.8 3 ( (2.0 6 ( (1.0 1 ( (0.0 0 ( (0.0 1 ( (0.0 0 ( (0.0 0 (0.0 CK 98 7 (7.1 8 ( ( ( (0.9 2 (1.9 K (1.0 1 ( (0.0 0 ( (0.0 0 ( (1.0 1 ( (0.0 0 ( (0.9 1 ( (1.0 3 ( (0.0 0 ( (0.9 2 ( (0.0 2 ( (1.0 1 ( (0.9 2 ( (0.0 0 ( (0.0 0 ( (0.0 0 ( (1.0 3 ( (0.0 0 ( (1.9 3 (2.8 ASTGOT (4.0 5 ( (0.0 0 ( (1.9 3 (2.8 ALTGPT (4.0 5 ( (0.0 0 ( (1.9 3 (2.8 LDH (2.0 3 ( (3.9 5 ( (0.0 0 (0.0 γ-gtp 99 2 (2.0 3 ( (0.0 0 ( (0.9 3 (2.8 ALP (3.0 3 ( (1.9 2 ( (1.9 2 ( (2.0 2 ( (0.0 0 ( (0.0 0 ( (6.1 6 ( (0.0 3 ( (3.8 4 ( (3.0 3 ( (0.0 0 ( (0.0 0 ( (2.1 2 ( (0.0 0 ( (0.0 0 ( (0.0 1 ( (1.0 1 ( (0.0 0 (0.0 BUN (2.0 2 ( (2.0 3 ( (0.9 1 ( (0.0 0 ( (0.0 0 ( (0.0 0 ( (1.1 1 ( (0.0 0 ( (0.0 0 (0.0 Na (0.0 0 ( (0.0 0 ( (0.0 0 (0.0 Cl (0.0 0 ( (0.0 0 ( (0.0 0 ( (0.0 0 ( (0.0 0 ( (0.9 3 ( (1.0 1 ( (0.0 0 ( (0.0 0 (0.0 a PPX BROM ( % (TABLE :1-152

32 PPX PPX 5% AST(GOTALT(GPT CK 119PPX ( 5% 7 ( ( ( ( (( ( mg/ 112 ( 23. (U/l ( 173 ( 310 ( 92 ( 5 ( ( ( mg/ 112 ( 4. (/mm ( 9000 ( ( 9400 ( 7 ( ( ( ( ( ( ( ( ( ( mg/ 112 ( 23. (U/l ( 108 ( 282 ( 111 ( CK CK 7 ( ( ( mg/ 112 ( 17. (mg/dl ( 107 ( 214 ( 162 ( ( HbA1c4.8 ( ( mg/ 99 ( 11. (IU/l ( 20 ( 34 ( 41 ( 20(7/3 12. (IU/l ( 36 ( 55 ( 72 ( 40(7/3 3 ( ( mg/ 112 ( 4. (/mm ( ( 4300 ( 5200 ( WBC 8 ( ( ( mg/ 109 ( 4. (/mm ( 3100 ( 2800 ( 2000 ( 7/273400( 4 ( ( mg/ 112 ( 4. (/mm ( 8400 ( 9700 ( 7800 ( 12. (IU/l ( 95 ( 51 ( 13 ( 17. (mg/dl ( 100 ( 145 ( 102 ( ( 6

33 PPX ( ( 5% 6 ( ( mg/ 112 ( 23. (U/l ( 267 ( 132 ( 138 ( ( ( ( ( ( ( ( ( ( ( ( mg/ 112 ( 4. (/mm ( 7440 ( ( 7110 ( mg/ 112 ( 17. (mg/dl ( 102 ( 123 ( 86 ( 6 ( ( ( mg/ 6 ( 11. (IU/l ( 467 ( 25 ( 1 (12/ (IU/l ( 343 ( 15 ( (12/ (mg/dl ( 298 ( 158 ( 5 ( ( mg/ 103 ( 23. (U/l ( 101 ( 144 ( 107 ( CK 11. (IU/l ( 19 ( 48 ( 28 ( 12. (IU/l ( 19 ( 73 ( 31 ( 17. (mg/dl ( 135 ( 156 ( 127 ( (( (U/l ( 259 ( 322 ( 213 ( CK (IU/l ( 39 ( 34 ( 41 ( 8 1 CK GOT 23GPT (U/l ( 283 ( 627 ( 237 ( 11. (IU/l ( 43 ( 50 ( 35 ( 12. (IU/l ( 55 ( 34 ( 12 ( 23. (U/l ( 144 ( 503 ( 132 ( ( 17. (mg/dl ( 101 ( 147 ( 91 ( 23. (U/l ( 119 ( 153 ( 79 ( 6 ( ( ( ( mg/ 104 ( 4. (/mm ( ( 8500 ( a : : : 6 ( mg/ 112 ( 6 ( ( ( mg/ 112 ( mg/ 112 ( mg/ 70 ( 7 ( ( ( ( mg/ 98 (

34 vi BROM PPX PPX a 120 PPX BROM (0.0 0 ( (1.0 2 ( (1.9 3 ( (1.0 1 ( (0.0 0 ( (0.0 0 (0.0 a PPX BROM ( % (TABLE : PPX ( ( ( (101 BROM ( ( ( (102 (mmhg ( ( ( (107 PPX ( ( ( (101 BROM ( ( ( (102 (mmhg ( ( ( (106 PPX ( ( ( (101 BROM ( ( ( (103 / ( ( ( (106 S.D.( PPX BROM (TABLE :

35 ( ( ( T/ 6T/ ( ( 7 ( ( PPX BROM ( mg/ 6 ( mg/ ( 6 ( 84 ( ( ( BROM ( mg/ ( 6 ( ( ( ( ( PPX : BROM : vii 123 PPX BROM 2 1 (1.0% 2 (2.1% a 123 PPX BROM 99 1 (1.0 2 ( (2.1 2 ( (0.0 0 (0.0 a ( % PPX BROM (TABLE :1-156

36 L-DOPA 124 * 12 BROM ( 1.25mg/ ( 6 ( ( ( ( ( ( 2 ( PACPVC PVC PACPVC 4 PVC BROM ( 1.25mg/ ( 6 ( ( ( ( 10 ( ST PPX ( mg/ 7 ( ( 112 ( ( PPX ( ( mg/ 112 ( TV1V6 V5V6 T * PPX: BROM: ** : : : L-DOPA mg/ mg/ UPDRS Part II Part III UPDRS Part II Part III UPDRS Part II AUC Part III AUCUPDRS Part IIII Part IIV Modified Hoehn & Yahr 61.8% 47.1% 28.0% -157

37 % 76.9% 85.3% 69.6% 54.6% 72.4% 3 1 L-DOPA 0.25 mg/ 4.5 mg/ L-DOPA -158

38 III L-DOPA L-DOPA L-DOPA III L-DOPA L-DOPA (1 30 (2 on Modified Hoehn & Yahr 24 (3 L-DOPA end-of-dose wearing-off 30 (4 on off (5 (1, (2 1 2 L-DOPA 3 2 (3 1-II III - 50 / -NYHA III IV Al-pLDH AST(GOT (4 100 mmhg 20 mmhg ( lisuride 2 60 (6 (7 90 (

39 L-DOPA III ( [ ] II UPDRS UPDRS =0.025 = UPDRS t = % mg0.25 mg0.5 mg1 mg 2.5 mg5 mg (1 30 L-DOPA ( mg 30mg 2 1 mg (1 (2 (3 (4 (5 (6 (7 (8 (9 (10 ( a 2.5 b b a1 1 b mg (1 L-DOPA L-DOPA short acting (2 - lisuride MAO

40 L-DOPA III ( Visit X 12 Mini-Mental-State FSQEuroQoL Disability ratings a b aupdrs Part IPart IIPart IVModified Schwab-England Disability ScaleTimed-walking testmodified Hoehn & Yahr Modified Hoehn & Yahr Visit bupdrs Part IIIon FSQFunctional Status Questionnaire UPDRS Part II on off on UPDRS Part III UPDRS Part II [visit 914]AUC UPDRS Part III [visit 914]AUC UPDRS Part II13 UPDRS Part III14 on UPDRS Part II UPDRS Part I UPDRS Part IV( UPDRS L-DOPA 1 Modified Schwab-England disability scale (on off Modified Hoehn & Yahr (on off Timed-walking test off %off Mini-Mental-State EuroQoLFSQFunctional Status Questionnaire UPDRS Part I Part IV

41 L-DOPA III ( UPDRS Part IIon off Part III 5% 3 Wilcoxon 3 Kruskal-Wallis Wilcoxon Wilcoxon 2-3 Kruskal-Wallis Wilcoxon 2 - LOCFLast Observation Carried Forward UPDRS Kruskal-Wallis Wilcoxon 0.05 Principal investigator mg/kg 0.3 mg/kg L-DOPA II mg mg1.5 mg mg1.25 mg mg mg 3 3 a PPX 80 BROM PPX 24 BROM PPX 56 BROM PPX

42 PPX BROM 80 ( ( ( ( ( ( ( ( ( ( ( ( (2.5 0 (0.0 1 (1.2 3 (1.2 4 ( ( ( ( (3.8 0 (0.0 2 (2.4 5 (2.0 9 ( (6.0 7 ( (8.5 3 (3.8 1 (1.2 4 (4.8 8 (3.2 a 1 (1.2 0 (0.0 1 (1.2 2 (0.8 2 (2.5 1 (1.2 1 (1.2 4 (1.6 a 127 % PPX BROM Table 8.1:1 PPX 9 BROM 6 9 PPX 15 BROM i PPPer-Protocol 11 1 L-DOPA i 100mg/ ii iii i ii 75% 125% PP PP -163

43 PPPer-Protocol 59%non-compliant PP a PPX L-DOPA 1 100mg/ 10 4 BROM 2 L-DOPA Modopar CR Madopar 250mg L-DOPA 100mg/ 3 ( 61 BROM 10 4 PPX budipine L-DOPA 2 100mg/ budipine 30.6%non-compliant (50mg / ( 48.5%non-compliant L-DOPA Visit mg/ aper-protocol PPX BROM (Table 8.2:1, 8.2.7:1 ITTIntent-to-treat PPX 1 ITT PPX PP ITT 246 PP LOCFLast Observation Carried Forward PPX BROM ITT 246 ITT 1 PPX 79 PPX 1 BROM PP 223 PP 23 PPX 73 PPX 6 BROM 76 BROM ITTIntent-to-treatPPPer-protocolPPX BROM 9-164

44 b ITT 246 PPX 79 BROM Broca-index PP ITT PPX BROM ( ( ( ( ( ( ( ( (36.6 p=0.752 c ( ( ( ( ( ( ( ( ( ( ( (25.6 S.D p= d 78 ( ( ( ( (1.3 2 (2.4 2 (2.4 5 (2.0 p=0.665 c cm S.D p= a,d cm S.D p= d kg S.D p= d kg S.D p= d ( ( ( ( ( ( ( ( ( ( ( (18.3 p=0.410 c 15 9 ( (6.0 7 ( (8.5 0 (0.0 1 (1.2 1 (1.2 2 ( II 38 ( ( ( (44.7 IIIII 21 ( ( ( (32.1 (Hoehn & Yahr III 19 ( ( ( (20.7 p=0.197 c IV 1 (1.3 2 (2.4 3 (3.6 6 (2.4 UPDRS Part II b p= e UPDRS Part III p= e UPDRS p= e 300 mg 19 ( ( ( ( mg 35 ( ( ( (41.1 L-DOPA mg 14 ( ( ( ( mg 7 (8.9 5 ( ( (8.9 p=0.719 f mg 4 (5.1 7 ( ( ( ( ( ( ( ( ( ( (55.3 p=0.676 c 71 ( ( ( ( ( ( ( (11.0 p=0.608 c a p=0.0115b on off (Table 8.3.1:1 c Cochran-Mantel-Haenszel d ANOVAe Kruskal-Wallis f 2 PPX BROM ( % -165

45 c % 6 PPX 2 BROM PPX 3 BROM 1 d PPX 4.5 mg/ 38.9%28/72 BROM 30 mg/ 55.1% 43/ %47/74 S.D.PPX mg/ BROM mg/ PPX BROM 129 (mg/ PPX 38.9% (28/ BROM 55.1% (43/ % (47/ appx 4.5 mg/ BROM 30 mg/ S.D. (Page 147, Appendix , Table 4.3.1, e i UPDRS Part II ITT 13 on off UPDRS Part II 130 UPDRS Part II PPX 2.50BROM p= PPX BROM p=0.0002p=0.0171ppx BROM (p PPX PP ITT 2 (p= ( 131 PPX 79 BROM ITT UPDRS Part II 25%, 75% (% ( (8.50, (4.50, (6.00, 0.00 (46.67, (8.00, (5.25, (5.00, 0.50 (42.63, 5.41 a p PPX vs BROM vs PPX vs BROM (8.50, (7.50, (2.50, 1.50 (20.00, a3 Kruskal-Wallis 2 Wilcoxon (Table :1, :2 PPX BROM -166

46 PPPer-Protocol UPDRS Part II 25%, 75% Wilcoxon ( ( PPX (8.50, (4.50, (6.00, (8.00, (7.50, (2.50, 1.50 p= PPX (Table :1 ii UPDRS Part III ( ITT on 14 UPDRS Part III 132 UPDRS Part III PPX 6.00BROM p= PPX BROM p=0.0006p=0.0113ppx BROM PPX PP ITT PPX 132ITT UPDRS Part III 25%, 75% a ( (% p (17.00, (9.00, (14.00, 1.00 (61.54, BROM (23.00, (10.00, (13.50, 0.00 (50.00, PPX vs BROM vs PPX vs BROM (17.00, (14.00, (8.00, 3.00 (30.00, a3 Kruskal-Wallis 2 Wilcoxon (Table :1, :2 PPX BROM 133PPPer-Protocol UPDRS Part III 25%, 75% Wilcoxon ( ( PPX (17.00, (9.00, (14.00, (16.00, (12.00, (8.00, 3.00 p= PPX (Table :1 iii UPDRS Part II Part III UPDRS Part II 10 4 PPX UPDRS Part II % % % % mg/ 4 36 PPX BROM -167

47 mg/ UPDRS Part II PPX BROM UPDRS Part UPDRS Part II PPX 79 BROM PPX Wilcoxon ( p PPX BROM (Table :2 10UPDRS Part II UPDRS Part III PPX UPDRS Part III mg/ 36 BROM mg/ 36 UPDRS Part III PPX BROM UPDRS Part III PPX Wilcoxon ( p PPX BROM (Table :3 11UPDRS Part III -168

48 iv UPDRS Part II Part III AUCUPDRS Part IV Part IIV UPDRS Part II Part III AUCarea under the curveudprs Part IV UPDRS Part I Part IV 137 AUC UPDRS Part II Part III AUC AUC visit visit UPDRS Part II AUC PPX BROM PPX BROM PPX BROM UPDRS Part III AUC Part II AUC PPX BROM PPX BROM UPDRS Part IV UPDRS Part IV 11 3 UPDRS Part IV L-DOPA A. B. C. 3 A. L-DOPA L-DOPA Peak dose dyskinesia L-DOPA over dose L-DOPA 7 L-DOPA L-DOPA UPDRS Part IV A PPX S.D.BROM PPX 40.0%BROM 45.2% 26.5% PPX BROM L-DOPA L-DOPA UPDRS Part IV A 54 Kondo T, Prog. Med 19, (

49 Part IV A Dyskinesias PPX S.D BROM S.D S.D PPX BROM B. L-DOPA wearingoff, on-off wearing-off L-DOPA 5 L-DOPA L-DOPA 1 12 L-DOPA L-DOPA 7,55 L-DOPA L-DOPA on off on-off UPDRS Part IV B off off B 135 PPX BROM PPX BROM 135Part IV B Clinical Fluctuations PPX S.D BROM S.D S.D PPX BROM C UPDRS Part IV C 136 PPX BROM UPDRS Part IV C 55 Fabbrini G et al: Ann Neurol 21: 370,

50 PPX BROM UPDRS Part IV C 3 136Part IV C Other Complications PPX S.D BROM S.D S.D PPX BROM UPDRS Part IV AB C A PPX BROM B PPX BROM C 3 A,B,C UPDRS Part IV UPDRS Part IV PPX UPDRS Part IIV UPDRS Part IPart IIPart III Part IV PPX BROM PPX BROM PPX BROM -171

51 UPDRS Part II AUC, Part III AUC, UPDRS Part IV Part IIV PPX BROM p= UPDRS Part II PPX vs p= AUC 25% BROM vs p= % PPX vs BROM p= p= UPDRS Part III PPX vs p= AUC 25% BROM vs p= % PPX vs BROM p= p= UPDRS Part IV PPX vs p= % BROM vs p= % PPX vs BROM p= p= UPDRS Part IIV PPX vs p= % BROM vs p= % PPX vs BROM p= aupdrs IV - 3 Kruskal-Wallis 2 Wilcoxon PPX BROM (Table :1, :2 v Timed-walking test Timed-walking test 138 PPX 2.00 BROM PPX BROM 138Timed-walking test PPX BROM a p= Timed-walking PPX vs p= test ( 25% BROM vs p= % PPX vs BROM p= a3 Kruskal-Wallis 2 Wilcoxon (Table :1, :2 PPX BROM vi 1 off off 1 off (% 1 off 139 off 3 off PPX 15.42%BROM 8.33% 2.25% PPX PPX 15% BROM -172

52 off PPX BROM a p= off PPX vs p= (% 25% BROM vs p= % PPX vs BROM p= a3 Kruskal-Wallis 2 Wilcoxon (Table :1, :2 PPX BROM vii 140 PPX 1 L-DOPA (p0.001 (p0.001 BROM 1 L-DOPA

53 (UPDRS Part I1 L-DOPA off Mini-Mental-State Modified Schwab-England Modified Hoehn Yahr PPX BROM p 16 ( ( ( UPDRS Part I 23 ( ( (36.1 PPX vs ( ( (34.9 BROM vs (3.8 1 (1.2 1 (1.2 PPX vs BROM ( ( ( / 50 ( ( (85.5 PPX vs L-DOPA 0 (0.0 0 (0.0 0 (0.0 BROM vs PPX vs BROM ( ( ( ( ( (57.8 PPX vs ( ( (22.9 BROM vs (3.8 1 (1.2 1 (1.2 PPX vs BROM ( ( ( ( ( (42.2 PPX vs off 35 ( ( (32.5 BROM vs ( (3.6 7 (8.4 PPX vs BROM ( ( ( Mini-Mental-State 29 ( ( (33.7 PPX vs ( ( (26.5 BROM vs (8.9 4 (4.8 5 (6.0 PPX vs BROM ( ( ( ( ( (59.0 PPX vs ( (6.0 5 (6.0 BROM vs Modified Schwab- England scale (on Modified Schwab- England scale (off PPX vs BROM ( ( ( ( ( (59.0 PPX vs ( ( (21.7 BROM vs (0.0 0 (0.0 0 (0.0 PPX vs BROM ( ( ( ( ( (43.4 PPX vs ( ( (26.5 BROM vs (0.0 0 (0.0 1 (1.2 PPX vs BROM (6.3 8 (9.5 8 ( ( ( (73.5 PPX vs Modified Hoehn & Yahr on 22 ( ( (16.9 BROM vs (0.0 0 (0.0 0 (0.0 PPX vs BROM (7.6 7 ( ( Modified Hoehn & 44 ( ( (59.0 PPX vs Yahr off 29 ( ( (24.1 BROM vs (0.0 0 (0.0 1 (1.2 PPX vs BROM PPX BROM ( % (Table :3, :4-174

54 viii UPDRS Part II Part III UPDRS Part II 13 UPDRS Part III UPDRS Part II p PPX BROM BROM 141UPDRS Part II p PPX BROM PPX vs BROM vs PPX vs BROM 33 ( ( (22.9 Speech 33 ( ( ( ( ( ( ( ( (19.3 Salivation 44 ( ( ( ( ( ( ( ( (14.5 Swallowing 53 ( ( ( (8.9 7 ( ( ( ( (25.3 Handwriting 24 ( ( ( ( ( ( Cutting food and 32 ( ( (24.1 handling utensils 33 ( ( ( ( ( ( ( ( (25.3 Dressing 32 ( ( ( ( ( ( ( ( (21.7 Hygiene 38 ( ( ( ( ( ( Turning in bed and 33 ( ( (36.1 adjusting bedclothes 32 ( ( ( ( ( (22.9 Falling 24 ( ( (25.3 (unrelated to freezing 47 ( ( ( ( ( ( ( ( (18.1 Freezing when walking 34 ( ( ( ( ( ( ( ( (20.5 Walking 33 ( ( ( ( ( ( ( ( (32.5 Tremor 24 ( ( ( ( ( ( Sensory complaints related 36 ( ( (30.1 to parkinsonism 34 ( ( ( ( ( (19.3 PPX BROM ( % (Table 13:5,6-175

55 UPDRS Part III UPDRS Part III p PPX BROM PPX BROM 142UPDRS Part III p PPX BROM PPX vs BROM vs PPX vs BROM 23 ( ( (19.3 Speech 46 ( ( ( ( ( ( ( ( (22.9 Facial expression 35 ( ( ( ( ( ( ( ( (32.5 Tremor at rest 32 ( ( ( ( ( ( Action or postural 20 ( ( (21.7 tremor of hands 51 ( ( ( ( ( ( ( ( (33.7 Rigidity 25 ( ( ( ( ( ( ( ( (42.2 Finger tap 29 ( ( ( ( ( ( ( ( (38.6 Hand movements 32 ( ( ( ( ( ( Rapid alternating 40 ( ( (39.8 movements of hands 29 ( ( ( ( ( ( ( ( (33.7 Leg agility 29 ( ( ( ( ( ( ( ( (16.9 Arising from chair 45 ( ( ( ( ( ( ( ( (18.1 Posture 51 ( ( ( (7.6 9 ( ( ( ( (16.9 Gait 45 ( ( ( ( ( ( ( ( (19.3 Postural stability 54 ( ( ( ( ( ( Body bradykinesia and 36 ( ( (26.5 hypokinesia 35 ( ( ( ( ( (20.5 PPX BROM (Table 13:7, 8 ( % -176