Background
Methods
Study design
Study subjects
Endpoints
Statistical issues
Short-term period
Long-term period
Safety outcomes
Sample size
Results
Patient disposition and demographics
All | First randomization | Second randomization | |||||
---|---|---|---|---|---|---|---|
PRM | Placebo | PRM | Placebo | ||||
N
|
172
|
86
|
86
|
127
|
39
| ||
Characteristic | Visit | ||||||
Age (years) | 1 | Mean (SD) | 63.8 (9.3) | 63.4 (9.8) | 64.2 (8.8) | 63.4 (9.6) | 64.3 (8.3) |
Sex |
N (%) female | 128 (74.4%) | 63 (73.3%) | 65 (75.6%) | 96 (75.6%) | 28 (71.8%) | |
Race* |
N (%) white | 170 (98.8%) | 84 (97.7%) | 86 (100.0%) | 125 (98.4%) | 39 (100.0%) | |
Height (m) | 1 | Mean (SD) | 1.63 (0.08) | 1.64 (0.09) | 1.63 (0.08) | 1.64 (0.09) | 1.62 (0.08) |
Weight (kg) | 1 | Mean (SD) | 71.4 (13.1) | 71.0 (14.0) | 71.8 (12.2) | 70.9 (13.4) | 72.8 (12.3) |
BMI (kg/m2) | 1 | Mean (SD) | 26.7 (4.1) | 26.4 (3.9) | 27.1 (4.3) | 26.4 (4.0) | 27.7 (4.5) |
Taking any medications | 1 |
N (%) | 17 (9.9%) | 6 (7.0%) | 11 (12.8%) | 10 (7.9%) | 6 (15.4%) |
Taking codeine† | 1 |
N (%) | 29 (16.9%) | 13 (15.1%) | 16 (18.6%) | 21 (16.5%) | 8 (20.5%) |
Taking codeine | 2 |
N (%) | 26 (15.1%) | 16 (18.6%) | 10 (11.6%) | 21 (16.5%) | 5 (12.8%) |
Confirmed codeine analgesic | 2 |
N (%) | 15 (8.7%) | 8 (9.3%) | 7 (8.1%) | 11 (8.7%) | 4 (10.3%) |
All | First randomization | Second randomization | |||||
---|---|---|---|---|---|---|---|
PRM | Placebo | PRM | Placebo | ||||
N
|
281
|
137
|
144
|
198
|
75
| ||
Characteristic | Visit | ||||||
Age (years) | 1 | Mean (SD) | 71.0 (4.1) | 71.1 (3.8) | 70.9 (4.4) | 70.9 (3.9) | 70.9 (4.4) |
Sex |
N (%) female | 182 (64.8%) | 89 (65.0%) | 93 (64.6%) | 128 (64.6%) | 50 (66.7%) | |
Race* |
N (%) white | 280 (100.0%) | 137 (100.0%) | 143 (100.0%) | 198 (100.0%) | 74 (100.0%) | |
Height (m) | 1 | Mean (SD) | 1.65 (0.09) | 1.65 (0.09) | 1.64 (0.09) | 1.65 (0.09) | 1.64 (0.09) |
Weight (kg) | 1 | Mean (SD) | 73.3 (13.0) | 73.1 (14.1) | 73.6 (11.8) | 73.2 (13.2) | 74.1 (12.6) |
BMI (kg/m2) | 1 | Mean (SD) | 27.0 (3.8) | 26.8 (3.6) | 27.3 (3.9) | 26.8 (3.6) | 27.7 (4.2) |
Taking any medications | 1 |
N (%) | 265 (94.3%) | 130 (94.9%) | 135 (93.8%) | 187 (94.4%) | 70 (93.3%) |
Taking codeine† | 1 |
N (%) | 73 (26.2%) | 35 (25.7%) | 38 (26.6%) | 50 (25.5%) | 20 (26.7%) |
Taking codeine | 2 |
N (%) | 58 (20.6%) | 28 (20.4%) | 30 (20.8%) | 40 (20.2%) | 16 (21.3%) |
Confirmed codeine analgesic | 2 |
N (%) | 43 (15.3%) | 18 (13.1%) | 25 (17.4%) | 25 (12.6%) | 16 (21.3%) |
Efficacy
Primary efficacy variable
Treatment | Treatment effect difference PRM - placebo; (95% confidence interval) |
Pvalue* effect PRM versus placebo | ||
---|---|---|---|---|
PRM | Placebo | |||
Low excretor population
| ||||
N
| 86 | 86 | ||
Baseline: mean (SD) | 74.1 (54.9) | 75.5 (58.5) | ||
Treatment: mean (SD) | 65.1 (59.9) | 66.5 (51.6) | ||
Change from baseline: mean (SD) | -9.0 (50.5) | -9.0 (48.7) | -0.6 (-14.0, 12.7) | 0.924 |
65-80 year population
| ||||
N
| 137 | 144 | ||
Baseline: mean (SD) | 76.7 (63.7) | 72.5 (51.4) | ||
Treatment: mean (SD) | 57.6 (51.8) | 70.9 (54.0) | ||
Change from baseline: mean (SD) | -19.1 (47.3) | -1.7 (47.8) | -15.6 (-25.3, -6.0), | 0.002 |
Other variables in the short-term period
Treatment effects | |||||
---|---|---|---|---|---|
Change from baseline Mean (SD) | Short term | Long term * | |||
Visit 3 | Visit 7 | Estimate (95% CI)
P -value | Estimate (95% CI)
P -value | ||
N
MAX
| PRM | 86 | 99 | ||
Placebo | 86 | 31 | |||
Sleep latency | PRM | -9.0 (50.5) | -23.6 (42.1) | -0.6 (-14.0, 12.7) | -6.7 (-16.4, 3.0) |
(min) | Placebo | -9.0 (48.7) | -19.4 (79.5) |
P = 0.924 |
P = 0.174 |
Sleep | PRM | -0.27 (0.77) | -0.31 (1.08) | -0.16 (-0.39, 0.08) | -0.04 (-0.24, 0.16) |
maintenance | Placebo | -0.12 (1.04) | -0.34 (0.71) |
P = 0.185 |
P = 0.677 |
Total sleep | PRM | 0.34 (0.88) | 0.70 (1.00) | 9.1 (-6.1, 24.4) | 13.1 (1.0, 25.2) |
time (h) | Placebo | 0.20 (0.91) | 0.47 (1.18) |
P = 0.236 |
P = 0.035 |
Sleep onset | PRM | -0.15 (0.89) | -0.46 (0.79) | -0.08 (-0.33, 0.17) | -0.16 (-0.34, 0.03) |
(h) | Placebo | -0.05 (0.80) | -0.24 (1.11) |
P = 0.530 |
P = 0.096 |
Sleep offset | PRM | 0.09 (0.79) | 0.08 (0.84) | 0.04 (-0.18, 0.25) | 0.07 (-0.09, 0.22) |
(h) | Placebo | 0.10 (0.75) | 0.20 (1.00) |
P = 0.744 |
P = 0.392 |
Refreshed on | PRM | -0.09 (0.46) | -0.23 (0.43) | -0.01 (-0.13, 0.11) | -0.03 (-0.12, 0.06) |
waking | Placebo | -0.09 (0.40) | -0.29 (0.47) |
P = 0.830 |
P = 0.540 |
Morning | PRM | -0.14 (0.67) | -0.42 (0.65) | 0.01 (-0.18, 0.19) | -0.06 (-0.19, 0.08) |
alertness | Placebo | -0.19 (0.63) | -0.35 (0.73) |
P = 0.936 |
P = 0.426 |
Sleep quality | PRM | -0.20 (0.67) | -0.43 (0.70) | -0.04 (-0.24, 0.16) | -0.08 (-0.23, 0.06) |
Placebo | -0.16 (0.70) | -0.34 (0.60) |
P = 0.688 |
P = 0.266 |
Change from baseline Mean (SD) | Treatment effects | ||||
---|---|---|---|---|---|
Short term | Long term * | ||||
Visit 3 | Visit 7 | Estimate (95% CI)
P -value | Estimate (95% CI)
P -value | ||
NMAX
| PRM | 86 | 101 | ||
Placebo | 86 | 31 | |||
PSQI | PRM | -2.13 (2.89) | -3.78 (3.65) | -0.40 (-1.19, 0.38) | -0.66 (-1.30, -0.01) |
Global score | Placebo | -1.62 (2.59) | -2.94 (2.91) |
P = 0.313 |
P = 0.046 |
PSQI | PRM | -0.30 (0.83) | -0.72 (0.80) | -0.02 (-0.22, 0.19) | -0.13 (-0.29, 0.02) |
Component 1 | Placebo | -0.26 (0.67) | -0.42 (1.06) |
P = 0.884 |
P = 0.086 |
PSQI | PRM | -0.37 (0.72) | -0.90 (1.02) | -0.12 (-0.33, 0.10) | -0.17 (-0.36, 0.02) |
Component 2 | Placebo | -0.26 (0.71) | -0.68 (0.79) |
P = 0.278 |
P = 0.080 |
PSQI | PRM | -0.50 (0.89) | -0.87 (1.04) | -0.04 (-0.29, 0.21) | -0.13 (-0.33, 0.06) |
Component 3 | Placebo | -0.44 (0.83) | -0.65 (0.88) |
P = 0.735 |
P = 0.169 |
PSQI | PRM | -0.40 (1.09) | -0.89 (1.25) | 0.09 (-0.20, 0.39) | -0.01 (-0.24, 0.21) |
Component 4 | Placebo | -0.45 (0.99) | -0.77 (1.12) |
P = 0.537 |
P = 0.918 |
PSQI | PRM | -0.09 (0.33) | -0.01 (0.48) | -0.10 (-0.18, -0.03) | -0.01 (-0.06, 0.05) |
Component 5 | Placebo | 0.03 (0.32) | -0.03 (0.31) |
P = 0.008 |
P = 0.811 |
PSQI | PRM | 0.00 (0.00) | 0.00 (0.00) |
†
|
†
|
Component 6 | Placebo | 0.00 (0.00) | 0.00 (0.00) | ||
PSQI | PRM | -0.47 (0.82) | -0.39 (0.99) | -0.17 (-0.35, 0.01) | -0.06 (-0.17, 0.05) |
Component 7 | Placebo | -0.24 (0.87) | -0.39 (0.84) |
P = 0.067 |
P = 0.283 |
PSQI | PRM | -18.3 (52.4) | -41.3 (59.0) | -0.2 (-13.2, 12.8) | -11.6 (-22.0, -1.1) |
Question 2 | Placebo | -18.5 (51.7) | -33.1 (92.2) |
P = 0.980 |
P = 0.030 |
PSQI | PRM | 0.63 (1.10) | 1.11 (1.33) | 0.09 (-0.20, 0.38) | 0.17 (-0.07, 0.41) |
Question 4 | Placebo | 0.51 (0.94) | 0.81 (1.08) |
P = 0.539 |
P = 0.164 |
CGI-I‡
| PRM | 3.22 (1.05) | 2.50 (1.19) | -0.15 (-0.46, 0.16) | -0.25 (-0.49, -0.01) |
Placebo | 3.31 (0.98) | 3.06 (1.21) |
P = 0.339 |
P = 0.042 | |
WHO-5 | PRM | 1.27 (3.53) | 1.79 (4.27) | 1.21 (0.22, 2.20), | 0.91 (0.16, 1.66) |
Index | Placebo | -0.03 (3.45) | 1.06 (3.56) |
P = 0.016 |
P = 0.017 |
Treatment effects | |||||
---|---|---|---|---|---|
Change from baseline Mean (SD) | Short term | Long term * | |||
Visit 3 | Visit 7 | Estimate (95% CI)
P -value | Estimate (95% CI)
P -value | ||
NMAX
| PRM | 137 | 159 | ||
Placebo | 144 | 61 | |||
Sleep latency | PRM | -19.1 (47.3) | -25.9 (46.4) | -15.6 (-25.3, -6.0) | -14.5 (-21.4, -7.7) |
(min) | Placebo | -1.7 (47.8) | -8.3 (61.5) |
P = 0.002 | P < 0.001 |
Sleep | PRM | -0.24 (0.80) | -0.31 (0.94) | -0.17 (-0.33, 0.00) | -0.09 (-0.22, 0.03) |
maintenance | Placebo | -0.09 (0.78) | -0.20 (0.70) |
P = 0.046 |
P = 0.148 |
Total sleep | PRM | 0.34 (0.75) | 0.64 (0.99) | 7.0 (-3.4, 17.4) | 7.5 (-0.7, 15.7) |
time (h) | Placebo | 0.20 (0.79) | 0.41 (1.06) |
P = 0.186 |
P = 0.073 |
Sleep onset | PRM | -0.22 (0.80) | -0.41 (0.75) | -0.22 (-0.39, -0.05) | -0.21 (-0.33, -0.08) |
(hours) | Placebo | 0.00 (0.71) | -0.12 (1.06) |
P = 0.012 |
P = 0.002 |
Sleep offset | PRM | 0.03 (0.81) | 0.03 (0.84) | -0.16 (-0.33, 0.02) | -0.12 (-0.24, 0.00) |
(h) | Placebo | 0.19 (0.79) | 0.21 (0.91) |
P = 0.076 |
P = 0.051 |
Refreshed on | PRM | -0.10 (0.36) | -0.22 (0.42) | 0.00 (-0.08, 0.08) | -0.06 (-0.12, 0.00) |
waking | Placebo | -0.09 (0.37) | -0.11 (0.42) |
P = 0.994 |
P = 0.053 |
Morning | PRM | -0.18 (0.52) | -0.36 (0.69) | -0.04 (-0.16, 0.07) | -0.10 (-0.19, -0.01) |
alertness | Placebo | -0.11 (0.51) | -0.09 (0.60) |
P = 0.453 |
P = 0.032 |
PRM | -0.20 (0.56) | -0.39 (0.71) | -0.06 (-0.19, 0.07) | -0.08 (-0.18, 0.01) | |
Sleep quality | Placebo | -0.12 (0.57) | -0.17 (0.54) |
P = 0.356 |
P = 0.082 |
Change from baseline Mean (SD) | Treatment effects | ||||
---|---|---|---|---|---|
Short term | Long term * | ||||
Visit 3 | Visit 7 | Estimate (95% CI)
P -value | Estimate (95% CI)
P -value | ||
N
MAX
| PRM | 136 | 164 | ||
Placebo | 144 | 62 | |||
PSQI | PRM | -1.86 (2.93) | -3.34 (3.37) | -0.64 (-1.25, -0.02) | -0.70 (-1.17, -0.23) |
Global score | Placebo | -1.19 (2.53) | -2.08 (2.92) |
P = 0.042 |
P = 0.003 |
PSQI | PRM | -0.32 (0.71) | -0.59 (0.82) | -0.09 (-0.23, 0.05) | -0.15 (-0.25, -0.04) |
Component 1 | Placebo | -0.19 (0.65) | -0.34 (0.85) |
P = 0.217 |
P = 0.006 |
PSQI | PRM | -0.43 (0.87) | -0.75 (0.99) | -0.23 (-0.41, -0.04) | -0.24 (-0.38, -0.10) |
Component 2 | Placebo | -0.22 (0.74) | -0.52 (0.95) |
P = 0.018 |
P = 0.001 |
PSQI | PRM | -0.48 (0.89) | -0.86 (1.08) | -0.10 (-0.29, 0.10) | -0.10 (-0.25, 0.05) |
Component 3 | Placebo | -0.40 (0.89) | -0.65 (0.96) |
P = 0.328 |
P = 0.177 |
PSQI | PRM | -0.32 (0.96) | -0.79 (1.22) | -0.05 (-0.27, 0.17) | -0.10 (-0.26, 0.06) |
Component 4 | Placebo | -0.29 (1.04) | -0.47 (1.05) |
P = 0.638 |
P = 0.236 |
PSQI | PRM | 0.01 (0.41) | -0.04 (0.43) | -0.05 (-0.13, 0.02) | 0.00 (-0.05, 0.05) |
Component 5 | Placebo | 0.03 (0.39) | -0.02 (0.42) |
P = 0.162 |
P = 0.973 |
PSQI | PRM | -0.01 (0.12) | 0.01 (0.18) |
†
|
†
|
Component 6 | Placebo | 0.00 (0.00) | 0.00 (0.00) | ||
PSQI | PRM | -0.30 (0.95) | -0.31 (0.94) | -0.04 (-0.19, 0.11) | -0.07 (-0.17, 0.02) |
Component 7 | Placebo | -0.12 (0.69) | -0.10 (0.86) |
P = 0.636 |
P = 0.137 |
PSQI | PRM | -25.4 (50.9) | -32.7 (49.3) | -13.7 (-23.5, -3.9) | -12.1 (-19.1, -5.1) |
Question 2 | Placebo | -8.9 (48.0) | -19.0 (65.8) |
P = 0.006 |
P = 0.001 |
PSQI | PRM | 0.58 (1.03) | 1.05 (1.29) | 0.10 (-0.13, 0.33) | 0.14 (-0.04, 0.32) |
Question 4 | Placebo | 0.48 (1.00) | 0.71 (1.08) |
P = 0.381 |
P = 0.120 |
PRM | 3.34 (1.17) | 2.70 (1.17) | -0.12 (-0.37, 0.14) | -0.20 (-0.38, -0.02) | |
CGI-I‡
| Placebo | 3.54 (0.85) | 3.19 (1.11) |
P = 0.364 |
P = 0.027 |
WHO-5 | PRM | 1.02 (3.73) | 1.51 (4.05) | 0.42 (-0.34, 1.18), | 0.55 (-0.02, 1.13) |
Index | Placebo | 0.27 (3.15) | 0.35 (4.21) |
P = 0.281 |
P = 0.058 |
Long-term period
Safety
Treatment period
Category of AE | Treatment period | Extension period | ||
---|---|---|---|---|
PRM | Placebo | PRM | Placebo | |
No. of patients | 394 | 395 | 534 | 177 |
Any AE | 136 (34.5%) | 142 (35.9%) | 394 (73.8%) | 136 (76.8%) |
Any SAE | 1 (0.3%) | 3 (0.8%) | 15 (2.8%) | 9 (5.1%) |
SAE leading to death | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (0.6%) |
DAE | 9 (2.3%) | 8 (2.0%) | 30 (5.6%) | 12 (6.8%) |
Drug-related AE* | 17 (5.3%) | 19 (6.1%) | 56 (12.9%) | 24 (17.3%) |
Drug-related SAE* | 0 (0.0%) | 0 (0.0%) | 1 (0.2%) | 0 (0.0%) |
System organ class | Treatment period | Extension period | ||
---|---|---|---|---|
PRM(n= 394) | Placebo(n= 395) | PRM(n= 534) | Placebo(n= 177) | |
Infections and infestations | 38 (9.6) | 43 (10.9) | 176 (33.0) | 60 (33.9) |
Gastrointestinal disorders | 18 (4.6) | 31 (7.8) | 113 (21.2) | 37 (20.9) |
Musculoskeletal and connective tissue disorders | 21 (5.3) | 21 (5.3) | 113 (21.2) | 34 (19.2) |
Nervous system disorders | 19 (4.8) | 23 (5.8) | 47 (8.8) | 19 (10.7) |
Respiratory, thoracic and mediastinal disorders | 12 (3.0) | 16 (4.1) | 47 (8.8) | 18 (10.2) |
Skin and subcutaneous tissue disorders | 12 (3.0) | 9 (2.3) | 43 (8.1) | 13 (7.3) |
Injury, poisoning and procedural complications | 8 (2.0) | 2 (0.5) | 35 (6.6) | 13 (7.3) |
Renal and urinary disorders | 9 (2.3) | 4 (1.0) | 29 (5.4) | 7 (4.0) |
General disorders and administration site disorders | 5 (1.3) | 5 (1.3) | 28 (5.2) | 16 (9.0) |
Investigations | 5 (1.3) | 7 (1.8) | 24 (4.5) | 9 (5.1) |
Eye disorders | 5 (1.3) | 1 (0.3) | 20 (3.7) | 6 (3.4) |
Psychiatric disorders | 5 (1.3) | 4 (1.0) | 17 (3.2) | 13 (7.3) |
Vascular disorders | 2 (0.5) | 0 (0) | 16 (3.0) | 5 (2.8) |
Cardiac disorders | 0 (0) | 1 (0.3) | 15 (2.8) | 2 (1.1) |
Ear and labyrinth disorders | 0 (0) | 1 (0.3) | 13 (2.4) | 2 (1.1) |
Reproductive system and breast disorders | 3 (0.8) | 3 (0.8) | 12 (2.2) | 1 (0.6) |
Metabolism and nutrition disorders | 1 (0.3) | 2 (0.5) | 7 (1.3) | 4 (2.3) |
Surgical and medical procedures | 1 (0.3) | 2 (0.5) | 7 (1.3) | 6 (3.4) |