Table 3 Meta-regression analyses of study design-, intervention-, and patient-related covariates associated with study outcomes
All-cause discontinuation | Discontinuation due to AE | Cognitive function | Global change | Neuropsychiatric symptoms | Functional ability | Proportion patients SAE | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
N | Constant (95%CI) Log OR (95%CI) | R2 | N | Constant (95%CI) Log OR (95%CI) | R2 | N | Constant (95%CI) Diff SMD (95%CI) | R2 | N | Constant (95%CI) Diff SMD (95%CI) | R2 | N | Constant (95%CI) Diff SMD (95%CI) | R2 | N | Constant (95%CI) Diff SMD (95%CI) | R2 | N | Constant (95%CI) Log OR (95%CI) | R2 | |
Study site | |||||||||||||||||||||
Single site (ref.) | 18 | −0.026 (−1.145, 1.093) | 0 | 14 | 2.314 (− 0.927, 5.555) | 0.11 | 17 | 0.157 (−0.441, 0.754) | 0 | – | – | – | 15 | 0.093 (−0.758, 0.944) | 0 | – | – | – | – | – | – |
Multi-site | −0.007 (−1.139, 1.125) | −2.162 (−5.414, 1.089) | −0.007 (− 0.610, 0.595) | – | – | – | 0.072 (− 0.783, 0.926) | – | – | – | – | – | – | ||||||||
Lead-in period | |||||||||||||||||||||
No (ref.) | 18 | 0.071 (− 0.147, 0.290) | 0.27 | 14 | 0.292 (−0.073, 0.657) | 0 | 17 | 0.134 (0.033, 0.236) | 0 | 10 | 0.104 (−0.037, 0.245) | 0.05 | 15 | 0.185 (0.082, 0.288) | 0 | 10 | 0.057 (−0.075, 0.189) | 0 | 10 | −0.131 (− 0.524, 0.262) | 0 |
Yes | −0.223 (− 0.543, 0.097) | −0.267 (− 0.799, 0.265) | 0.033 (− 0.117, 0.182) | 0.087 (− 0.084, 0.258) | −0.046 (− 0.198, 0.107) | 0.016 (− 0.160, 0.191) | 0.021 (− 0.505, 0.546) | ||||||||||||||
Placebo lead-in period | |||||||||||||||||||||
No (ref.) | 18 | 0.071 (− 0.147, 0.290) | 0.27 | 14 | 0.292 (−0.073, 0.657) | 0 | 17 | 0.134 (0.033, 0.236) | 0 | 10 | 0.104 (−0.037, 0.245) | 0.05 | 15 | 0.185 (0.082, 0.288) | 0 | 10 | 0.057 (−0.075, 0.189) | 0 | 10 | −0.131 (− 0.524, 0.262) | 0 |
Yes | −0.223 (− 0.543, 0.097) | −0.267 (− 0.799, 0.265) | 0.033 (− 0.117, 0.182) | 0.087 (− 0.084, 0.258) | −0.046 (− 0.198, 0.107) | 0.016 (− 0.160, 0.191) | 0.021 (−0.505, 0.546) | ||||||||||||||
Statistical analysis | |||||||||||||||||||||
ITT (ref.) | – | – | – | – | – | – | 17 | 0.162 (0.069, 0.256) | 0 | 10 | 0.192 (0.100, 0.283) | 0.15 | 15 | 0.006 (−0.153, 0.164) | 0.72 | 10 | 0.102 (0.002, 0.202) | 0.10 | – | – | – |
Non-ITT | – | – | −0.036 (− 0.190, 0.118) | −0.104 (− 0.282, 0.073) | 0.089 (0.011, 0.358)* | − 0.104 (− 0.273, 0.066) | – | ||||||||||||||
Intervention | |||||||||||||||||||||
Monotherapy (ref.) | 18 | 0.054 (−0.195, 0.302) | 0 | 14 | 0.244 (−0.166, 0.654) | 0 | 17 | 0.177 (0.068, 0.286) | 0 | 10 | 0.168 (0.040, 0.295) | 0 | 15 | 0.212 (0.103, 0.321) | 0.02 | 10 | 0.089 (− 0.038, 0.216) | 0 | 10 | −0.032 (− 0.407, 0.343) | 0 |
Combination ChEI | −0.157 (− 0.492, 0.178) | −0.138 (− 0.689, 0.413) | − 0.052 (− 0.202, 0.097) | −0.009 (− 0.181, 0.164) | − 0.090 (− 0.236, 0.057) | −0.043 (− 0.217, 0.131) | − 0.163 (− 0.677, 0.350) | ||||||||||||||
Dose | |||||||||||||||||||||
20 mg/day (ref.) | 18 | −0.049 (− 0.230, 0.132) | 0 | 14 | 0.126 (−0.154, 0.406) | 0 | 17 | 0.141 (0.061, 0.220) | 0 | 10 | 0.148 (0.059, 0.237) | 0 | 15 | 0.160 (0.079, 0.242) | 0 | 10 | 0.064 (−0.032, 0.159) | 0 | 10 | −0.182 (− 0.428, 0.063) | 0.50 |
28 mg/day | 0.136 (−0.388, 0.661) | 0.376 (−0.478, 1.229) | 0.072 (− 0.162, 0.306) | 0.102 (− 0.126, 0.330) | 0.038 (−0.205, 0.280) | 0.019 (−0.240, 0.277) | 0.470 (−0.207, 1.147) | ||||||||||||||
Dosage | |||||||||||||||||||||
Fixed (ref.) | 18 | −0.049 (− 0.230, 0.132) | 0 | 14 | 0.126 (− 0.154, 0.406) | 0 | 17 | 0.141 (0.061, 0.220) | 0 | 10 | 0.148 (0.059, 0.237) | 0 | 15 | 0.160 (0.079, 0.242) | 0 | 10 | 0.064 (−0.032, 0.159) | 0 | 10 | −0.182 (− 0.428, 0.063) | 0.50 |
Flexible | 0.136 (−0.388, 0.661) | 0.376 (−0.478, 1.229) | 0.072 (−0.162, 0.306) | 0.102 (−0.126, 0.330) | 0.038 (−0.205, 0.280) | 0.019 (−0.240, 0.277) | 0.470 (−0.207, 1.147) | ||||||||||||||
Regimen | |||||||||||||||||||||
QD (ref.) | 18 | 0.057 (−0.206, 0.320) | 0 | 14 | 0.263 (−0.209, 0.735) | 0 | 17 | 0.077 (−0.025, 0.180) | 0.48 | 10 | 0.109 (−0.030, 0.248) | 0 | 15 | 0.123 (0.010, 0.237) | 0 | 10 | −0.023 (− 0.152, 0.106) | 0.36 | 10 | 0.050 (−0.391, 0.491) | 0 |
BID | −0.149 (− 0.487, 0.189) | −0.143 (− 0.718, 0.432) | 0.125 (− 0.011, 0.260) | 0.084 (−0.089, 0.257) | 0.070 (−0.080, 0.219) | 0.137 (−0.024, 0.297) | −0.245 (− 0.776, 0.286) | ||||||||||||||
Length (weeks) | |||||||||||||||||||||
Intercept | 18 | −0.076 (− 0.296, 0.144) | 0 | 14 | 0.124 (−0.225, 0.473) | 0 | 17 | 0.145 (0.046, 0.243) | 0 | 10 | 0.270 (−0.170, 0.709) | 0 | 15 | 0.196 (0.101, 0.292) | 0.01 | 10 | 0.045 (−0.062, 0.152) | 0 | 10 | −0.038 (− 0.361, 0.286) | 0 |
0.001 (−0.002, 0.004) | 0.001 (−0.004, 0.006) | 0.000 (−0.002, 0.002) | −0.005 (− 0.024, 0.014) | −0.001 (− 0.002, 0.001) | 0.001 (− 0.001, 0.002) | 0.001 (−0.005, 0.002) | |||||||||||||||
Age (years) | |||||||||||||||||||||
Intercept | 18 | −1.674 (−6.563, 3.216) | 0 | 14 | −0.115 (−7.371, 7.141) | 0 | 17 | −0.084 (−2.235, 2.068) | 0 | 10 | −0.586 (−3.310, 2.137) | 0 | 15 | −1.287 (−3.409, 0.836) | 0.12 | 10 | −1.304 (−4.816, 2.208) | 0 | 10 | 4.223 (−6.002, 14.448) | 0 |
0.021 (−0.042, 0.085) | 0.004 (−0.091, 0.098) | 0.003 (−0.025, 0.031) | 0.010 (−0.026, 0.045) | 0.019 (−0.009, 0.047) | 0.018 (−0.028, 0.064) | −0.057 (− 0.190, 0.077) | |||||||||||||||
Women (%) | |||||||||||||||||||||
Intercept | 18 | 0.117 (−0.428, 0.662) | 0 | 14 | 0.359 (−0.463, 1.182) | 0 | 17 | 0.128 (−0.147, 0.403) | 0 | 10 | −0.099 (− 0.880, 0.681) | 0 | 15 | −0.038 (− 0.293, 0.216) | 0.35 | 10 | 0.076 (− 0.215, 0.367) | 0 | 10 | −0.378 (− 0.950, 0.194) | 0 |
−0.003 (− 0.012, 0.006) | −0.003 (− 0.017, 0.010) | 0.0004 (− 0.004, 0.005) | 0.004 (−0.008, 0.016) | 0.003 (−0.001, 0.008) | −0.0002 (− 0.005, 0.005) | 0.005 (−0.005, 0.015) | |||||||||||||||
AD baseline severity | |||||||||||||||||||||
Mild-moderate (ref.) | 18 | 0.117 (−0.170, 0.404) | 0.19 | 14 | 0.338 (−0.063, 0.839) | 0.03 | 17 | 0.125 (−0.004, 0.254) | 0 | 10 | 0.139 (−0.007, 0.286) | 0 | 15 | 0.089 (−0.032, 0.210) | 0.24 | 10 | 0.029 (−0.03, 0.160) | 0 | 10 | −0.051 (− 0.414, 0.312) | 0 |
Moderate-severe | −0.219 (− 0.566, 0.127) | −0.334 (− 0.887, 0.219) | 0.036 (− 0.122, 0.194) | 0.036 (−0.144, 0.215) | 0.110 (−0.039, 0.259) | 0.063 (−0.108, 0.235) | −0.142 (− 0.663, 0.380) | ||||||||||||||
Baseline cognitive function (mean) | |||||||||||||||||||||
Intercept | 18 | −0.298 (− 0.797, 0.202) | 0.12 | 14 | −0.299 (−1.080, 0.481) | 0.09 | 17 | 0.261 (0.032, 0.490) | 0.02 | 10 | 0.215 (−0.068, 0.499) | 0 | 15 | 0.387 (0.185, 0.589) | 0.88 | 10 | 0.198 (−0.071, 0.467) | 0.01 | 10 | −0.125 (−1.011, 0.761) | 0 |
0.006 (−0.005, 0.016) | 0.010 (−0.006, 0.026) | −0.003 (− 0.007, 0.002) | −0.001 (− 0.007, 0.005) | − 0.005 (− 0.009, − 0.001)** | −0.003 (− 0.008, 0.003) | 0.0001 (−0.016, 0.017) | |||||||||||||||
Baseline neuropsychiatric symptoms severity (mean) | |||||||||||||||||||||
Intercept | 15 | −0.101 (− 0.530, 0.339) | 0 | 12 | 0.163 (−0.505, 0.831) | 0 | 15 | 0.210 (0.023, 0.397) | 0 | 9 | 0.228 (−0.009, 0.466) | 0 | 15 | 0.010 (−0.174, 0.193) | 0.37 | 10 | 0.204 (−0.038, 0.447) | 0.09 | 9 | −0.178 (− 0.910, 0.555) | 0 |
0.006 (−0.027, 0.040) | 0.0003 (−0.051, 0.052) | −0.005 (− 0.020, 0.010) | −0.006 (− 0.024, 0.012) | 0.013 (− 0.002, 0.028) | −0.013 (− 0.034, 0.008) | 0.010 (− 0.063, 0.084) | |||||||||||||||
Baseline functional ability (mean) | |||||||||||||||||||||
Intercept | 11 | −1.897 (−3.685, −0.110) | 0.68 | 11 | −2.536 (−5.183, 0.111) | 0.47 | 12 | 0.140 (−0.492, 0.771) | 0 | 8 | 0.040 (−0.413, 0.492) | 0 | 10 | 0.461 (−0.253, 1.175) | 0 | 10 | 0.702 (−0.061, 1.466) | 0.44 | 8 | −0.831 (−2.931, 1.269) | 0 |
0.028 (0.001, 0.055)* | 0.041 (0.001, 0.081)* | 0.000 (−0.010, 0.010) | 0.002 (−0.006, 0.009) | −0.005 (− 0.016, 0.006) | −0.010 (− 0.021, 0.002) | 0.011 (− 0.020, 0.042) | |||||||||||||||
Type of scale | |||||||||||||||||||||
Intercept (ref.) | – | – | – | – | – | – | 17 | ADAS-Cog 0.138 (0.003, 0.272) | 0 | 10 | CIBIC-Plus 0.151 (0.062, 0.241) | 0 | – | – | – | – | – | – | – | – | – |
– | – | – | – | – | – | MMSE 0.019 (−0.176, 0.214) | CGI 0.087 (−0.154, 0.328) | – | – | – | – | – | – | – | – | – | |||||
SIB 0.016 (−0.173, 0.204) | |||||||||||||||||||||
Sponsor | |||||||||||||||||||||
Independent (ref.) | 18 | 0.133 (−0.275, 0.541) | 0 | 14 | 0.306 (−0.524, 1.136) | 0 | 17 | 0.183 (−0.019, 0.385) | 0 | – | – | – | 15 | 0.178 (−0.026, 0.381) | 0 | 10 | 0.151 (−0.136, 0.439) | 0 | 10 | −0.343 (− 0.921, 0.235) | 0 |
Industry | −0.199 (− 0.645, 0.248) | −0.155 (−1.035, 0.725) | −0.040 (− 0.257, 0.178) | – | – | – | − 0.016 (− 0.236, 0.204) | −0.093 (− 0.394, 0.208) | 0.274 (− 0.366, 0.914) | ||||||||||||