Introduction
Methods
Study design and patients
Outcome measures
Statistics
Results
Baseline characteristics and dosage of drugs
(A) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
(a) Combination therapy with levodopa | |||||||||||||
Elderly | Non-elderly | ||||||||||||
Rotigotine | Placebo | Rotigotine | Placebo | ||||||||||
n
|
n
|
n
|
n
| ||||||||||
Age (years), mean ± SD | 86 | 73.6 ± 2.8 | 68 | 73.2 ± 2.7 | 164 | 61.3 ± 6.9 | 102 | 61.4 ± 7.0 | |||||
Weight (kg), mean ± SD | 86 | 52.7 ± 11.4 | 68 | 57.5 ± 10.6 | 164 | 56.1 ± 10.7 | 102 | 57.4 ± 9.4 | |||||
Duration of PD (years), mean ± SD | 86 | 7.4 ± 6.4 | 68 | 6.2 ± 3.5 | 164 | 7.0 ± 4.6 | 102 | 6.1 ± 3.9 | |||||
Levodopa dose at first intervention (mg), mean ± SD | 86 | 370.9 ± 180.9 | 68 | 342.6 ± 125.6 | 164 | 356.1 ± 145.5 | 102 | 354.2 ± 150.5 | |||||
Sex (male), number (%) | 86 | 33 (38.4) | 68 | 40 (58.8) | 164 | 62 (37.8) | 102 | 46 (45.1) | |||||
HY scale, number (%) | |||||||||||||
0 | – | – | – | – | – | – | – | – | |||||
1 | – | – | – | – | – | – | – | – | |||||
1.5 | – | – | – | – | – | – | – | – | |||||
2 | 86 | 16 (18.6) | 68 | 15 (22.1) | 164 | 40 (24.4) | 102 | 22 (21.6) | |||||
2.5 | 86 | 14 (16.3) | 68 | 12 (17.6) | 164 | 45 (27.4) | 102 | 25 (24.5) | |||||
3 | 86 | 47 (54.7) | 68 | 33 (48.5) | 164 | 65 (39.6) | 102 | 48 (47.1) | |||||
4 | 86 | 9 (10.5) | 68 | 8 (11.8) | 164 | 14 (8.5) | 102 | 7 (6.9) | |||||
5 | – | – | – | – | – | – | – | – | |||||
UPDRS score, mean ± SD | |||||||||||||
Part I | 86 | 1.07 ± 1.34 | 68 | 1.18 ± 1.54 | 164 | 0.92 ± 1.46 | 102 | 0.71 ± 1.03 | |||||
Part II (on) | 86 | 9.40 ± 5.59 | 68 | 9.24 ± 6.07 | 164 | 8.24 ± 5.84 | 102 | 7.20 ± 5.48 | |||||
Part II (off) | 49 | 14.51 ± 8.36 | 42 | 16.55 ± 9.12 | 116 | 16.00 ± 8.91 | 75 | 13.97 ± 6.82 | |||||
Part II (average) | 86 | 11.31 ± 5.78 | 68 | 11.57 ± 6.68 | 163 | 11.26 ± 6.36 | 102 | 10.12 ± 63.62 | |||||
Part III | 86 | 27.59 ± 11.38 | 68 | 26.91 ± 10.46 | 164 | 26.10 ± 11.09 | 102 | 25.30 ± 10.29 | |||||
Part II + III | 86 | 2.87 ± 2.76 | 67 | 2.58 ± 2.35 | 164 | 3.48 ± 2.81 | 102 | 3.34 ± 2.39 |
(b) Monotherapy | ||||||||
---|---|---|---|---|---|---|---|---|
Elderly | Non-elderly | |||||||
Rotigotine | Placebo | Rotigotine | Placebo | |||||
n
|
n
|
n
|
n
| |||||
Age (years), mean ± SD | 28 | 73.3 ± 2.6 | 31 | 74.2 ± 3.0 | 60 | 61.3 ± 6.9 | 57 | 61.8 ± 6.0 |
Weight (kg), mean ± SD | 28 | 55.2 ± 10.9 | 31 | 54.0 ± 8.7 | 60 | 56.8 ± 9.2 | 57 | 55.4 ± 9.5 |
Duration of PD (years), mean ± SD | 28 | 1.3 ± 1.3 | 31 | 1.5 ± 1.7 | 60 | 2.3 ± 1.9 | 57 | 2.0 ± 2.0 |
Sex (male), number (%) | 28 | 12 (42.9) | 31 | 14 (45.2) | 60 | 21 (35.0) | 57 | 23 (40.4) |
HY scale, number (%) | ||||||||
0 | – | – | – | – | – | – | – | – |
1 | 28 | 2 (7.1) | 31 | 0 (0.0) | 60 | 10 (16.7) | 57 | 5 (8.8) |
1.5 | 28 | 3 (10.7) | 31 | 5 (16.1) | 60 | 5 (8.3) | 57 | 7 (12.3) |
2 | 28 | 11 (39.3) | 31 | 14 (45.2) | 60 | 23 (38.3) | 57 | 22 (38.6) |
2.5 | 28 | 5 (17.9) | 31 | 5 (16.1) | 60 | 6 (10.0) | 57 | 7 (12.3) |
3 | 28 | 7 (25.0) | 31 | 7 (22.6) | 60 | 16 (26.7) | 57 | 16 (28.1) |
4 | – | – | – | – | – | – | – | – |
5 | – | – | – | – | – | – | – | – |
UPDRS score, mean ± SD | ||||||||
Part I | 28 | 1.00 ± 1.66 | 31 | 0.81 ± 1.01 | 60 | 0.67 ± 1.05 | 57 | 0.44 ± 0.78 |
Part II | 28 | 6.86 ± 4.72 | 31 | 8.03 ± 3.89 | 60 | 6.80 ± 3.56 | 57 | 7.12 ± 3.56 |
Part III | 28 | 20.89 ± 9.06 | 31 | 20.90 ± 9.16 | 60 | 19.82 ± 9.36 | 57 | 20.74 ± 9.77 |
Part II + III | 28 | 0.25 ± 0.44 | 31 | 0.23 ± 0.43 | 60 | 0.32 ± 0.54 | 57 | 0.18 ± 0.38 |
(B) | ||||||||
---|---|---|---|---|---|---|---|---|
(a) Combination therapy with levodopa | ||||||||
Elderly | Non-elderly | |||||||
Rotigotine | Placebo | Rotigotine | Placebo | |||||
n
|
n
|
n
|
n
| |||||
Age (years), mean ± SD | 87 | 73.6 ± 2.8 | 69 | 73.2 ± 2.6 | 168 | 61.4 ± 6.9 | 103 | 61.4 ± 7.0 |
Weight (kg), mean ± SD | 87 | 52.8 ± 11.4 | 69 | 57.3 ± 10.7 | 168 | 56.0 ± 10.6 | 103 | 57.5 ± 9.6 |
Duration of PD (years), mean ± SD | 87 | 7.3 ± 6.3 | 69 | 6.1 ± 3.5 | 168 | 6.9 ± 4.6 | 103 | 6.1 ± 3.9 |
Levodopa dose at first intervention (mg), mean ± SD | 87 | 370.1 ± 180.0 | 69 | 342.0 ± 124.7 | 168 | 365.4 ± 196.5 | 103 | 353.6 ± 149.8 |
Sex (male), number (%) | 87 | 34 (39.1) | 69 | 40 (58.0) | 168 | 62 (36.9) | 103 | 47 (45.6) |
HY scale, number (%) | ||||||||
0 | – | – | – | – | – | – | – | – |
1 | – | – | – | – | – | – | – | – |
1.5 | – | – | – | – | – | – | – | – |
2 | 87 | 16 (18.4) | 69 | 16 (23.2) | 168 | 41 (24.4) | 103 | 22 (21.4) |
2.5 | 87 | 14 (16.1) | 69 | 12 (17.4) | 168 | 45 (26.8) | 103 | 25 (24.3) |
3 | 87 | 48 (55.2) | 69 | 33 (47.8) | 168 | 66 (39.3) | 103 | 49 (47.6) |
4 | 87 | 9 (10.3) | 69 | 8 (11.6) | 168 | 16 (9.5) | 103 | 7 (6.8) |
5 | – | – | – | – | – | – | – | – |
UPDRS score, mean ± SD | ||||||||
Part I | 87 | 1.07 ± 1.33 | 69 | 1.19 ± 1.34 | 168 | 0.96 ± 1.49 | 103 | 0.70 ± 1.03 |
Part II (on) | 87 | 9.41 ± 5.56 | 69 | 9.17 ± 6.05 | 168 | 8.33 ± 5.91 | 103 | 7.18 ± 5.45 |
Part II (off) | 50 | 14.62 ± 8.31 | 43 | 16.40 ± 9.07 | 118 | 15.99 ± 8.84 | 76 | 13.95 ± 6.78 |
Part II (average) | 87 | 11.36 ± 5.76 | 69 | 11.51 ± 6.65 | 167 | 11.31 ± 6.35 | 103 | 10.11 ± 5.30 |
Part III | 87 | 27.77 ± 11.43 | 69 | 26.68 ± 10.56 | 168 | 26.47 ± 11.57 | 103 | 25.45 ± 10.34 |
Part II + III | 87 | 2.90 ± 2.76 | 68 | 2.60 ± 2.34 | 168 | 3.46 ± 2.81 | 103 | 3.35 ± 2.38 |
(b) Monotherapy | ||||||||
---|---|---|---|---|---|---|---|---|
Elderly | Non-elderly | |||||||
Rotigotine | Placebo | Rotigotine | Placebo | |||||
n
|
n
|
n
|
n
| |||||
Age (years), mean ± SD | 30 | 73.3 ± 2.5 | 31 | 74.2 ± 3.0 | 60 | 61.3 ± 6.9 | 59 | 61.6 ± 6.4 |
Weight (kg), mean ± SD | 30 | 55.0 ± 10.5 | 31 | 54.0 ± 8.7 | 60 | 56.8 ± 9.2 | 59 | 55.4 ± 9.6 |
Duration of PD (years), mean ± SD | 30 | 1.3 ± 1.3 | 31 | 1.5 ± 1.7 | 60 | 2.3 ± 1.9 | 59 | 2.1 ± 2.0 |
Sex (male), number (%) | 30 | 13 (43.3) | 31 | 14 (45.2) | 60 | 21 (35.0) | 59 | 25 (42.4) |
HY scale, number (%) | ||||||||
0 | – | – | – | – | – | – | – | – |
1 | 30 | 2 (6.7) | 31 | 0 (0.0) | 60 | 10 (16.7) | 59 | 5 (8.5) |
1.5 | 30 | 3 (10.0) | 31 | 5 (16.1) | 60 | 5 (8.3) | 59 | 7 (11.9) |
2 | 30 | 13 (43.3) | 31 | 14 (45.2) | 60 | 23 (38.3) | 59 | 23 (39.0) |
2.5 | 30 | 5 (16.7) | 31 | 5 (16.1) | 60 | 6 (10.0) | 59 | 7 (11.9) |
3 | 30 | 7 (23.3) | 31 | 7 (22.6) | 60 | 16 (26.7) | 59 | 17 (28.8) |
4 | – | – | – | – | – | – | – | – |
5 | – | – | – | – | – | – | – | – |
UPDRS score | ||||||||
Part I | 30 | 1.03 ± 1.61 | 31 | 0.81 ± 1.01 | 60 | 0.67 ± 1.05 | 59 | 0.42 ± 0.77 |
Part II | 30 | 6.97 ± 4.57 | 31 | 8.03 ± 3.89 | 60 | 6.80 ± 3.56 | 59 | 7.41 ± 4.64 |
Part III | 30 | 20.73 ± 8.78 | 31 | 20.90 ± 9.16 | 60 | 19.82 ± 9.36 | 59 | 21.36 ± 10.89 |
Part II + III | 30 | 0.30 ± 0.53 | 31 | 0.23 ± 0.43 | 60 | 0.32 ± 0.54 | 59 | 0.17 ± 0.38 |
Efficacy and safety in combination therapy in advanced stage PD patients
(A) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Adverse event (PT) | Combination therapy (rotigotine with levodopa) | Monotherapy (levodopa) | ||||||||
Elderly (n = 87) | Non-elderly (n = 168) |
p value†
| Elderly (n = 30) | Non-elderly (n = 60) |
p value†
| |||||
n
| Ratio (%) |
n
| Ratio (%) |
n
| Ratio (%) |
n
| Ratio (%) | |||
Total | 76 | 87.4 | 155 | 92.3 | 0.2034 | 24 | 80.0 | 54 | 90.0 | 0.1883 |
Application site reactions | 37 | 42.5 | 98 | 58.3 | 0.0165 | 10 | 33.3 | 32 | 53.3 | 0.0730 |
Nasopharyngitis | 17 | 19.5 | 29 | 17.3 | 0.6537 | 4 | 13.3 | 7 | 11.7 | 0.8200 |
Nauseaa
| 15 | 17.2 | 27 | 16.1 | 0.8113 | 2 | 6.7 | 19 | 31.7 | 0.0082 |
Dyskinesia | 9 | 10.3 | 30 | 17.9 | 0.1141 | 0 | 0.0 | 1 | 1.7 | 0.4770 |
Somnolencea
| 6 | 6.9 | 17 | 10.1 | 0.3944 | 6 | 20.0 | 7 | 11.7 | 0.2891 |
Visual hallucinationa
| 8 | 9.2 | 13 | 7.7 | 0.6882 | 1 | 3.3 | 2 | 3.3 | 1.0000 |
Vomitinga
| 6 | 6.9 | 14 | 8.3 | 0.6858 | 2 | 6.7 | 12 | 20.0 | 0.0999 |
Contusion | 7 | 8.0 | 6 | 3.6 | 0.1235 | 1 | 3.3 | 0 | 0.0 | 0.1550 |
Loss of appetite | 5 | 5.7 | 7 | 4.2 | 0.5721 | 2 | 6.7 | 3 | 5.0 | 0.7449 |
Blood creatinine phosphokinase increase | 3 | 3.4 | 9 | 5.4 | 0.4950 | 1 | 3.3 | 3 | 5.0 | 0.7176 |
Application site pruritus | 5 | 5.7 | 6 | 3.6 | 0.4175 | 0 | 0.0 | 0 | 0.0 | – |
Dizziness | 7 | 8.0 | 4 | 2.4 | 0.0348 | 0 | 0.0 | 0 | 0.0 | – |
Fall | 5 | 5.7 | 5 | 3.0 | 0.2798 | 0 | 0.0 | 0 | 0.0 | – |
Orthostatic hypotensiona
| 1 | 1.1 | 6 | 3.6 | 0.2618 | 0 | 0.0 | 0 | 0.0 | – |
Hallucinationa
| 4 | 4.6 | 2 | 1.2 | 0.0888 | 4 | 13.3 | 0 | 0.0 | 0.0038 |
Auditory hallucinationa
| 0 | 0.0 | 3 | 1.8 | 0.2099 | 0 | 0.0 | 0 | 0.0 | – |
Delusiona
| 1 | 1.1 | 2 | 1.2 | 0.9770 | 0 | 0.0 | 0 | 0.0 | – |
Sudden onset of sleepa
| 1 | 1.1 | 0 | 0.0 | 0.1638 | 1 | 3.3 | 0 | 0.0 | 0.1550 |
Constipation | 3 | 3.4 | 8 | 4.8 | 0.6245 | 3 | 10.0 | 9 | 15.0 | 0.5107 |
Insomnia | 0 | 0.0 | 6 | 3.6 | 0.0745 | 2 | 6.7 | 4 | 6.7 | 1.0000 |
Back pain | 0 | 0.0 | 6 | 3.6 | 0.0745 | 2 | 6.7 | 1 | 1.7 | 0.2129 |
Diarrhea | 2 | 2.3 | 2 | 1.2 | 0.4995 | 0 | 0.0 | 3 | 5.0 | 0.2129 |
Weight loss | 1 | 1.1 | 2 | 1.2 | 0.9770 | 2 | 6.7 | 0 | 0.0 | 0.0431 |
Peripheral edema | 1 | 1.1 | 1 | 0.6 | 0.6343 | 2 | 6.7 | 0 | 0.0 | 0.0431 |
Hypokalemia | 0 | 0.0 | 0 | 0.0 | – | 2 | 6.7 | 0 | 0.0 | 0.0431 |
(B) | ||||||||
---|---|---|---|---|---|---|---|---|
Adverse event (PT) | Combination therapy (levodopa with placebo) | Monotherapy (placebo) | ||||||
Elderly (n = 69) | Non-elderly (n = 103) | Elderly (n = 31) | Non-elderly (n = 59) | |||||
n
| Ratio (%) |
n
| Ratio (%) |
n
| Ratio (%) |
n
| Ratio (%) | |
Total | 53 | 76.8 | 83 | 80.6 | 19 | 61.3 | 46 | 78.0 |
Application site reactions | 9 | 13.0 | 17 | 16.5 | 6 | 19.4 | 14 | 23.7 |
Nasopharyngitis | 11 | 15.9 | 15 | 14.6 | 4 | 12.9 | 11 | 18.6 |
Nauseaa
| 4 | 5.8 | 8 | 7.8 | 0 | 0.0 | 5 | 8.5 |
Dyskinesia | 3 | 4.3 | 5 | 4.9 | 0 | 0.0 | 0 | 0.0 |
Somnolencea
| 1 | 1.4 | 2 | 1.9 | 1 | 3.2 | 3 | 5.1 |
Visual hallucinationa
| 2 | 2.9 | 3 | 2.9 | 0 | 0.0 | 0 | 0.0 |
Vomitinga
| 1 | 1.4 | 2 | 1.9 | 1 | 3.2 | 0 | 0.0 |
Contusion | 2 | 2.9 | 7 | 6.8 | 3 | 9.7 | 4 | 6.8 |
Loss of appetite | 1 | 1.4 | 2 | 1.9 | 0 | 0.0 | 0 | 0.0 |
Blood creatinine phosphokinase increase | 1 | 1.4 | 3 | 2.9 | 1 | 3.2 | 1 | 1.7 |
Application site pruritus | 2 | 2.9 | 2 | 1.9 | 0 | 0.0 | 0 | 0.0 |
Dizziness | 1 | 1.4 | 2 | 1.9 | 2 | 6.5 | 2 | 3.4 |
Fall | 2 | 2.9 | 6 | 5.8 | 1 | 3.2 | 1 | 1.7 |
Orthostatic hypotensiona
| 4 | 5.8 | 2 | 1.9 | 0 | 0.0 | 1 | 1.7 |
Hallucinationa
| 2 | 2.9 | 1 | 1.0 | 0 | 0.0 | 0 | 0.0 |
Auditory hallucinationa
| 0 | 0.0 | 1 | 1.0 | 0 | 0.0 | 0 | 0.0 |
Delusiona
| 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Sudden onset of sleepa
| 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Constipation | 2 | 2.9 | 1 | 1.0 | 1 | 3.2 | 4 | 6.8 |
Insomnia | 2 | 2.9 | 2 | 1.9 | 0 | 0.0 | 2 | 3.4 |
Back pain | 2 | 2.9 | 4 | 3.9 | 0 | 0.0 | 1 | 1.7 |
Diarrhea | 1 | 1.4 | 2 | 1.9 | 2 | 6.5 | 1 | 1.7 |
Weight loss | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Peripheral edema | 1 | 1.4 | 3 | 2.9 | 0 | 0.0 | 0 | 0.0 |
Hypokalemia | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Efficacy and safety in monotherapy in early stage PD patients
Discussion
Trial | Adverse event | Elderly/non-elderly | Group |
n
| Mean dosageb (mg/24 h) | SD |
---|---|---|---|---|---|---|
Combination therapy with levodopa | Application site reactionsa
| Elderly | Rotigotine | 45 | 10.1 | 4.5 |
Placebo | 16 | 8.3 | 5.5 | |||
Non-elderly | Rotigotine | 129 | 8.6 | 5.2 | ||
Placebo | 28 | 10.2 | 4.5 | |||
Visual hallucination/hallucination | Elderly | Rotigotine | 14 | 10.3 | 3.2 | |
Placebo | 4 | 14.0 | 2.3 | |||
Non-elderly | Rotigotine | 16 | 10.6 | 5.5 | ||
Placebo | 4 | 7.5 | 6.0 | |||
Somnolence | Elderly | Rotigotine | 6 | 8.7 | 4.5 | |
Placebo | 1 | 4.0 | – | |||
Non-elderly | Rotigotine | 17 | 7.4 | 4.8 | ||
Placebo | 2 | 3.0 | 1.4 | |||
Monotherapy | Application site reactionsa
| Elderly | Rotigotine | 12 | 8.7 | 4.8 |
Placebo | 6 | 7.0 | 4.1 | |||
Non-elderly | Rotigotine | 32 | 8.4 | 4.9 | ||
Placebo | 14 | 9.1 | 4.4 | |||
Visual hallucination/hallucination | Elderly | Rotigotine | 6 | 7.7 | 2.7 | |
Placebo | – | – | – | |||
Non-elderly | Rotigotine | 2 | 11.0 | 1.4 | ||
Placebo | – | – | – | |||
Somnolence | Elderly | Rotigotine | 6 | 8.7 | 5.9 | |
Placebo | 1 | 2.0 | – | |||
Non-elderly | Rotigotine | 7 | 5.7 | 3.7 | ||
Placebo | 3 | 10.7 | 5.0 |