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Table 3 Meta-regression analyses of study design-, intervention-, and patient-related covariates associated with study outcomes

From: Predictors of discontinuation, efficacy, and safety of memantine treatment for Alzheimer’s disease: meta-analysis and meta-regression of 18 randomized clinical trials involving 5004 patients

  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)  
  1. aType of scale used to evaluate the efficacy. Cognitive function: ADAS-Cog, MMSE or SIB; global change: CIBIC-Plus or CGI; neuropsychiatric symptoms: NPI; functional ability: ADCS-ADL
  2. *Statistically significant effect (p-value ≤0.05) ** statistically significant effect (p-value ≤0.01)
  3. AD Alzheimer’s disease, AE adverse event, CI confidence interval, Diff SMD difference of standardized mean difference, ITT intention to treat analysis, LoE lack of efficacy, Log OR Log odd ratio, N number of memantine-placebo comparisons, NA not applicable, PP per-protocol analysis, R2 proportion of variance explained by the covariate, SAE serious adverse event