Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer s disease. N Engl J Med 2012;366:893-903.
Online Supplement 1. Details of minimisation algorithm... 2 Table S1: Allocation probabilities according to pattern of previous assignments. 2 2. Details of MMRM Model... 3 3. Sensitivity analyses to explore the effect of discontinuation from treatment... 5 3.1. Statistical Methods... 5 3.2. Results and Discussion... 5 Table S2. Estimates of treatment differences in smmse and BADLS after 52 weeks with 95% CI for continuing and discontinuing donepezil and between adding active memantine and adding memantine placebo... 6 4. Supplementary Tables... 7 Table S3. Difference in smmse and BADLS at each visit between patients discontinuing treatment and continuing on treatment.... 7 Table S4. Estimate of average differences between trial arms in primary (smmse and BADLS) and secondary (NPI, DEMQOL-proxy and GHQ-12) outcomes over all time points with 95% CIs for the primary outcomes and 99% CIs for the secondary outcomes.... 9 Table S5. Classification of Serious Adverse Events (SAEs) by treatment arm... 10
1. Details of minimisation algorithm The first 80 patients recruited to the DOMINO trial were randomly allocated to one of the four treatment groups using a prepared list of simple randomised allocations. The reason for this was to maintain allocation concealment before the start of the minimisation algorithm. Starting with the eighty-first patient treatment was allocated by minimising treatment imbalance across four stratifying factors and using probability ratios that will vary according to the patterns of imbalance across the four treatment groups. There are four stratification factors to be incorporated into the minimisation algorithm: centre (15 strata); age at randomisation (3 strata: <60y, 60 to 74y, 75y and above); duration of donepezil treatment at randomisation (2 strata: 3 to <6m, 6m and above; standardised Mini-Mental State Examination (smmse) score at randomisation (2 strata 5-9, 10-13). The algorithm initially simply summed the previous treatment allocations across the four strata matching the new patient. For example, if a new patient was from Newcastle, aged 60 to 74 years, has received donepezil for less than six months, and has a smmse score of 8, the total allocations to each of the four treatments would be summed for Newcastle, age 60 to 74 years, donepezil for less than six months, and smmse score of between 5 and 8, thereby providing four separate totals, one for each treatment group. Assignment of treatment was then weighted according to the pattern of the four totals as shown in Table S1, where A, B, C, and D represent the four treatment totals placed in a non-decreasing order. (When two treatment totals are equal their ordering is immaterial). Table S1: Allocation probabilities according to pattern of previous assignments Pattern Description Treatment A B C D A = B = C = D A = B = C < D A = B < C = D A = B < C < D A < B = C = D A < B = C < D A < B < C = D A < B < C < D All four totals equal Lowest three totals equal Two lowest equal, and two highest equal Two lowest equal Highest three totals equal Middle two totals equal Highest two totals equal All unequal 0.25 0.32 0.42 0.42 0.76 0.76 0.76 0.76 0.25 0.32 0.42 0.42 0.12 0.25 0.32 0.12 0.06 0.25 0.04 0.04 0.06
2. Details of MMRM Model The primary analyses of the primary outcomes and the continuous secondary outcomes were conducted using multilevel modelling repeated measures regression (MMRM) adjusted for baseline and the four minimisation factors (centre, age, duration of donepezil and smmse score prior to randomisation). All non-missing at every visit, irrespective of whether the patient was still on trial medication or had switched to open-label treatment, were included in this analysis and there was no imputation of missing. Several models were fit to explore the effect of interactions. For patient i=1,,291 at follow-up visit j=1 (6 weeks), 2 (18 weeks), 3 (30 weeks), 4 (52 weeks), the full model was fit first: y ij = β 0 y i0 + s i + v 0j + ζ j + β 1 d i + β 2 m i + β 3 d i m i + v 1j d i + v 2j m i + ε ij, where: o y ij is the outcome of patient i at follow-up visit j; o y i0 is the baseline outcome for patient i, β 0 is the parameter representing the effect of the baseline outcome in the model; o v 0j is the parameter representing of the effect at follow-up visit j (v 04 =0 by design); o d i and m i are the indicator variables for whether patient i was randomised to continue (d i =1) or discontinue donepezil (d i =0) and randomised to start active (m i =1) or placebo memantine (m i =0); o β 1, β 2 and β 3 are the parameters representing the effect of donepezil, memantine and the interaction between donepezil and memantine; o v 1j and v 2j are the parameters representing the interactions between follow-up visit j and each of donepezil and memantine (v 14 =v 24 =0 by design); o ζ j is the random effect parameter assumed to follow a multivariate normal distribution ζ j ~ MVN(0, Σ); o ε ij is the simple error term assumed to follow a normal distribution ε ij ~ N(0,σ 0 2 ). No three-way interaction terms were included in the model to avoid convergence problems. s i is the term representing the adjustment for randomisation stratification factors for patient i: s i = γ 0 + γ 11 x 11i + γ 12 x 12i + γ 2 x 2i + γ 3 x 3i + γ 41 x 41i + γ 42 x 42i + + γ 414 x 414i where: o x 11i and x 12i are indicator variables for the age of patient i: less than 60 years, 60 to less than 75 years, 75 years or over; o x 2i is the indicator variable for duration of previous donepezil at randomisation of patient i: less than six months, greater or equal to six months; o x 3i is the indicator variable for baseline smmse score for patient i: 5 to 9 (severe dementia), 10 to 13 (moderate dementia); o x 41i, x 42i,,x 413i,x 414i are 14 indicator variables for the 15 different study centres for patient i; o the γ s are nuisance parameters representing the effects of the various stratification factors (γ 0 is fixed effects constant term).
Different covariate structures for Σ were compared using the Akaike Information Criterion. The model did not converge when the unstructured covariance matrix was used. The chosen model therefore used an independent covariance matrix, Σ ij =0 for i j and Σ ii =σ i 2. The model was subsequently fit setting v 1j =v 2j =0 to estimate the average treatment effect during follow-up for the between arm comparisons (including the interaction) and also fit setting v 1j =v 2j =β 3 =0 to estimate the average effect of each of donepezil and memantine during follow-up. The models were fit using maximum likelihood estimation using the modified Newton-Raphson algorithm in Stata version 12.0. The importance of individual terms in the models were evaluating using the Wald test. Further models were fit to evaluate whether the effect of donepezil and memantine on the primary outcomes differed by dementia severity (x 3i =1 for severe dementia and x 3i =0 for moderate dementia). The following model was fit (excluding the treatment interaction, setting β 3 =0): y ij = β 0 y i0 + s i + v 0j + ζ j + β 1 d i + β 2 m i + β 4 x 3i d i + β 5 x 3i m i + v 1j d i + v 2j m i + v 3j x 3i + v 4j x 3i d i + v 5j x 3i m i + ε ij, where: o β 4 and β 5 are the parameters representing the interactions between disease severity and each of donepezil and memantine; o v 3j is the parameter representing the interaction between follow-up visit j and dementia severity (v 34 =0 by design); o v 4j and v 5j are the parameters representing the three-way interactions between follow-up visit j, dementia severity and each of donepezil and memantine (v 44 =v 54 =0 by design). For both the smmse and BADLS, neither of the three-way interactions or the interaction between dementia severity and follow-up visit were significant at the 5% level and these terms were therefore dropped from the models. For both primary outcomes, the interactions between dementia severity and memantine was not significant at the 5% level, the same was true for the interaction between dementia severity and donepezil on BADLS. The interaction between donepezil and dementia severity was, however, significant on smmse showing that the effect of donepezil on smmse did differ by baseline dementia severity.
3. Sensitivity analyses to explore the effect of discontinuation from treatment 3.1. Statistical Methods Four different single imputation techniques were used: (1.) Imputing missing using a patient s last non-missing score (last observation carried forward - LOCF), (2.) Imputing after treatment discontinuation using a patient s last score before discontinuing treatment (treatment LOCF), (3.) Fitting a straight line to a patient s data before treatment discontinuation and imputing after discontinuation from the fitted line, (4.) Fitting an inverse exponential decline curve to a patient s data before treatment discontinuation and imputing after discontinuation from the fitted curve. The confidence intervals around the estimates using single imputation are artificially narrow as the false precision of the imputations has not been accounted for. (5.) Multiple imputation has been used to impute after discontinuation from treatment properly accounting for the artificial precision of the imputations. All stratification factors, the treatment, the visit week and the inverse exponential of the visit week are included in the imputation model. (6.) The primary analysis was repeated on a per protocol population defined as all patients having taken at least 70% of their treatment over the course of the trial, excluding any patients randomised in error or having taken open label donepezil or memantine concurrently with their study medication, and excluding any visits outside of the protocol-defined visit windows. (7.) The effect of donepezil and memantine was also evaluated using a simple unpaired t-test of the change in baseline as each visit. 3.2. Results and Discussion Patients in all treatment arms declined in cognitive function and activities of daily living over the course of the trial (Table S2). Imputation using LOCF underestimates the decline and therefore results in a bias in favour of the arm with the most drop-outs. Considerably more patients discontinued from treatment on the placebo arm and therefore TLOCF results in biased treatment effects that likely underestimate the true effects. Imputation assuming a linear or exponential decline is likely to be more appropriate than TLOCF, and both these analyses yield similar treatment estimates that are slightly smaller than those from the primary analysis. However, as shown in
Tables 4, patients who discontinue from treatment after 18 weeks have lower smmse and higher BADLS at the visit immediately prior to discontinuing. The observed case ITT analysis is therefore also an underestimate of the mean decline had all patients remained on treatment for the duration of the trial. No analysis can be considered to give uniformly unbiased treatment estimates but, with the exception of the results of the TLOCF analysis, the results are broadly consistent for each comparison suggesting the results of the primary analysis are robust estimates of the efficacy of donepezil and memantine in this patient population. Table S2. Estimates of treatment differences in smmse and BADLS after 52 weeks with 95% CI for continuing and discontinuing donepezil and between adding active memantine and adding memantine placebo smmse BADLS Endpoint and method of analysis Continue donepezil compared with discontinue Active memantine compared with Placebo Observed case ITT 1.9 (1.0, 2.8)* 0.7 (-0.2, 1.7) 1. LOCF 1.7 (0.9, 2.5)* 0.9 (0.1, 1.7)* Single 2. TLOCF 0.9 (0.1, 1.8)* 0.4 (-0.4, 1.2) imputation 3. Linear 1.2 (-0.1, 2.6) 0.5 (-0.8, 1.8) 4. Exponential 1.1 (-0.3, 2.4) 0.5 (-0.8, 1.9) 5. Multiple imputation 2.0 (0.9, 3.2)* 0.8 (-0.3, 2.0) 6. Per-protocol analysis 2.0 (0.8, 3.2)* 0.9 (-0.3, 2.1) 7. t-test change from baseline (mean / p-value) 1.57 / p=0.002 0.84 / p=0.096 Observed case ITT -2.9 (-4.9, -0.8)* -2.0 (-4.0, 0.1) 1. LOCF -2.5 (-4.3, -0.6)* -1.8 (-3.6, 0.1) Single 2. TLOCF -1.2 (-2.8, 0.5) -0.6 (-2.3, 1.1) imputation 3. Slope -3.2 (-6.3, -0.2)* -2.1 (-5.1, 1.0) 4. Exponential -2.6 (-5.7, 0.4) -1.7 (-4.8, 1.3) 5. Multiple imputation -3.2 (-5.3, -1.1)* -1.9 (-4.0, 0.2) 6. Per-protocol analysis -2.0 (-4.3, 0.3) -1.3 (-3.6, 1.0) 7. t-test change from baseline (mean / p-value) -2.44 / p=0.036-2.16 / p=0.064 It is assumed that there is no interaction. These results relate to primary objectives 1 and 2. The asterisk (*) indicates the 95% CI excludes 0. The first row shows the estimates for the primary observed case ITT analysis from Table 3 for comparison.
4. Supplementary Tables Table S3. Difference in smmse and BADLS at each visit between patients discontinuing treatment and continuing on treatment. Baseline 6 week 18 week 30 week 6 week 18 week 30 week 52 week smmse BADLS Remain on trial treatment? Difference (95% Mean Difference (95% N Mean (SD) N CI), p-value (SD) CI), p-value Comparison of before withdrawal of trial treatment for patients still on treatment Remain on treatment 271 9.1 (2.6) 0.7 (-0.5, 1.9) 271 27.4 (9.1) -3.1 (-7.2, 1.0) Withdraw before 6 weeks 20 8.4 (2.7) p=0.243 20 30.5 (8.7) p=0.136 Remain on treatment 218 9.3 (4.2) 1.4 (0.1, 2.6) 218 28.1 (9.4) -3.4 (-6.3, -0.6) Withdraw before 18 weeks 52 7.9 (3.6) p=0.135 52 31.6 (10.0) p=0.094 Remain on treatment 186 8.4 (4.5) 2.8 (1.2, 4.5) 186 30.6 (9.6) -7.6 (-11.3, -4.0) Withdraw before 30 weeks 33 5.5 (3.8) p=0.003 33 38.2 (11.1) p<0.001 Remain on treatment 154 7.9 (4.3) 2.5 (0.8, 4.1) 154 31.0 (10.0) -5.5 (-9.2, -1.8) Withdraw before 52 weeks 32 5.4 (4.2) p=0.006 32 36.4 (8.0) p=0.005 Comparison of after withdrawal from treatment Remained on treatment 271 9.0 (4.1) -3.1 (-5.3, -0.9) 271 28.8 (9.6) 5.3 (0.1, 10.4) Withdrawn before 6 weeks 20 (14)* 5.9 (3.1) p=0.007 20 (14)* 34.1 (8.3) p=0.050 Remained on treatment 219 7.9 (4.5) -2.8 (-4.3, -1.4) 219 31.8 (10.2) 6.3 (3.0, 9.6) Withdrawn before 18 weeks 72 (44)* 5.1 (3.9) p=0.010 72 (44)* 38.1 (9.5) p=0.011 Remained on treatment 186 7.5 (4.4) -3.7 (-4.9, -2.5) 186 31.9 (9.8) 8.1 (5.2, 11.0) Withdrawn before 30 weeks 105 (60)* 3.8 (3.5) p<0.001 105 (60)* 40.0 (9.9) p<0.001 Remained on treatment 154 5.8 (4.5) -3.3 (-4.6, -2.1) 154 34.9 (9.3) 8.8 (6.1, 11.5) Withdrawn before 52 weeks 137 (63)* 2.5 (3.4) p<0.001 137 (64)* 43.6 (9.1) p<0.001
N is the number of patients in each case and the difference is between the two groups at each visit. The p-value is from the test that the difference is equal to 0, adjusted for treatment group. *This is the total number of patients withdrawing from treatment with the total number attending the visit and contributing a non-missing score in parentheses. Standardised Mini-Mental State Examination (smmse, range 0 to 30, higher indicate better cognitive function); Bristol Activities of Daily Living Scale (BADLS, range 0 to 60, higher indicate greater functional impairment).
Table S4. Estimate of average differences between trial arms in primary (smmse and BADLS) and secondary (NPI, DEMQOL-proxy and GHQ-12) outcomes over all time points with 95% CIs for the primary outcomes and 99% CIs for the secondary outcomes. smmse (95% CI) BADLS (95% CI) NPI (99% CI) DEMQOL-proxy (99% CI) GHQ-12 (99% CI) Continue donepezil compared with discontinue when placebo memantine is started 2.4 (1.5, 3.2)* -4.1 (-5.8, -2.4)* -1.2 (-6.0, 3.5) -2.4 (-6.6, 1.9) -0.5 (-1.3, 0.2) Continue donepezil compared with discontinue when active memantine is started 1.5 (0.6, 2.3)* -2.0 (-3.7, -0.3)* -3.4 (-8.2, 1.4) -0.9 (-5.2, 3.4) -0.6 (-1.3, 0.2) Active memantine compared with placebo when donepezil is tapered and discontinued 1.7 (0.8, 2.5)* -2.6 (-4.3, -0.8)* -2.9 (-7.8, 1.9) 0.5 (-3.9, 4.9) -0.5 (-1.2, 0.3) Active memantine compared with placebo when donepezil is continued 0.8 (-0.1, 1.6) -0.5 (-2.2, 1.2) -5.1 (-9.8, -0.3)* 2.0 (-2.3, 6.2) -0.5 (-1.3, 0.3) The asterisk (*) indicates that the 95% or 99% CI excludes 0.
Table S5. Classification of Serious Adverse Events (SAEs) by treatment arm. Taper and discontinue donepezil Add placebo Add memantine memantine Continue donepezil Add placebo memantine Add memantine Fall 12 8 9 3 32 Respiratory tract infection 6 7 6 5 24 Urinary tract infection 2 8 5 5 20 Deterioration of AD 7 4 2 3 16 Behavioural symptoms of AD 4 2 5 4 15 Gastrointestinal 2 2 4 7 15 Stroke 3 1 5 3 12 Cardiac 1 1 1 2 5 Dysphagia 1 0 2 0 3 Psychosis 2 0 0 1 3 Unknown (died) 2 0 1 0 3 Venous embolus 1 1 0 1 3 Cancer 0 0 2 0 2 Syncope 0 0 2 0 2 GI Bleed 0 1 0 0 1 Social 0 1 0 0 1 Other 3 4 2 6 15 All SAEs 46 40 46 40 172 Drug error 2 2 1 1 6 Deaths 10 10 13 7 40 A total of 188 SAEs were reported by 123 patients during follow-up. Where more than one of the same type of event was reported by a patient, only the first in included in the table. Total