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Epilepsia, 41(9):1167-1178, 2000 Lippincott Williains & Wilkins, Inc., Baltimore 0 International Lcagoe Against Epilepsy Clinical Research A Multicenter, Randomized Clinical Study to Evaluate the Effect on Cognitive Function of Topiramate Compared with Valproate as Add-on Therapy to Carbamazepine in Patients with Partial-Onset Seizures *A. P. Aldenkamp, ‘fG. Baker, $0.G. Mulder, TD. Chadwick, §P
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  Epilepsia 41 9): 167-1178 2000 Lippincott Williains Wilkins, Inc., Baltimore International Lcagoe Against Epilepsy Clinical Research A Multicenter, Randomized Clinical Study to Evaluate the Effect on Cognitive Function of Topiramate Compared with Valproate as Add-on Therapy to Carbamazepine in Patients with Partial-Onset Seizures *A. P. Aldenkamp, ‘fG. Baker, 0. G. Mulder, TD. Chadwick, §P. Cooper, *J. Doelman, IIR. Duncan, ¶C. Gassmann-Mayer, ZG. J. de Haan, ¶C. Hughson, *J. Hulsman, J. Overweg, ¶G. Pledger, *T. W. Rentmeester, SH. Riaz, and S. Wroe *Departments o Neurology/Neuropsychology Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands; fDepartment of Neurosciences, Walton Hospital, Liverpool, United Kingdom; Department o Neurology, Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands; Department lf Behavioural Medicine, Hope Hospital, Saljord, United Kingdom; llDepartment f Neurology, Institute o Neurt,logical Sciences, Southern General Hospital, Glasgow, United Kingdom; YlThe R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, U.S.A.; and **The R. W. Johnson Pharmaceutical Research Institute, Bassersdorf, Switzerland Summary Purpose: This study compares the cognitive ef- fects of topiramate TPM) with those o valproate VPA) using efficacious doses of each drug when used as adjunctive therapy to carbamazepine CBZ). A key question of the study is to what extent a more gradual introduction of TPM improves tolerabil- ity and prevents cognitive impairment. Methods: The study is a multicenter, randomized, observer- blinded, parallel-group clinical trial with VPA or TPM given as first-line add-on therapy to steady-state treatment with CBZ. TPM is introduced at 25 mg and increased with weekly 25- mg/d increments to a minimum dosage of 200 mgld. The target dosage ranges from 200 to 400 mg/d for TPM and is 1800 mg/d for VPA. The study evaluates cognitive function changes from baseline to end point after 20 weeks of treatment) and during titration after 8 weeks of treatment). The primary outcome measure is the difference between the treatments TPM versus VPA) in change from baseline to end point and change from baseline to titration, using a 95 confidence interval approach. Results: For the 10 baseline-to-end point comparisons, one test measuring short-term verbal memory Rey Auditory Ver- bal Learning Test) yields a statistically significant difference between the treatments p = 0.02 , showing worsening for TPM and improvement of scores for VPA. The 10 baseline-to- titration comparisons also show one statistically significant dif- ference, again for a test measuring short-term memory Rec- ognition of Words; p = 0.04), showing a larger change in the negative direction for TPM. None of the mood tests or the test for subjective complaints shows statistically significant differ- ences between the treatments, although more scores are in the negative direction for TPM during titration. Conclusion: Although the pattern of changes in the negative direction seems consistent with clinical information, the differ- ences found between the treatments are small. An important finding of our study is that, when the results are compared with those of other studies, it is clear that gradual introduction of TPM can reduce the extent of cognitive impairment with a maximum of about 0.6 SD). Key Words: Adverse effects- Tapiramate-Cognitive function Topiramate (TPM), a sulfamate-substituted monosac- charide, is a novel compound that has a broad spectrum of antiepileptic activity (1). TPM has been used for ad- junctive treatment of partial-onset seizures in adults 2), and a recent study suggests that it may also be effective as monotherapy for adult epilepsy (3). In the adjunctive therapy trials, central nervous system (CNS)-related “cognitive” complaints were frequently reported, i.e., mental slowing, attentional deficits, speech problems, Such cognitive effects have been claimed for most of the antiepileptic drugs AEDs), although the clinical rel- Accepted April 25, 2000. Address correspondence and reprint requests to Dr. Albert P. Aldenkamp at Department of Behavioural Science, Epilepsy Centre Kempenhaeghe, P.O. Box 61, NL-5590 A.B. Heeze, The Netherlands. E-mail: aldenkampB @ kempenhaeghed and memory difficulties (443). 1167  1168 A P. ALDENKAMP ET AL evance is still under debate. Several studies have dem- onstrated the cognitive-impairing effects of chronic poly- pharmacy, independent of type of AEDs. The specificity of the cognitive effects per drug appeared much more difficult to demonstrate. Recent reviews 9,10) suggest that the cognitive effects of the commonly used AEDs carbamazepine CBZ) and valproate VPA) are mild to moderate and do not have a large clinical impact on patients’ daily lives, in contrast to the effects of “older” AEDs, in particular phenobarbitone and phenytoin. CBZ and VPA, therefore, are frequently used as the “gold standard” 1 j to examine the cognitive effects of newer AEDs. Of the newer AEDs, vigabatrin 12), oxcarbaz- epine 13), lamotrigine 14), and gabapentin 15) have been compared in equivalence studies with CBZ or VPA, and no significant differences have been found. The high number of patients with cognitive complaints in the aforementioned adjunctive therapy trials suggests that TPM may have a less favorable cognitive profile than the other new AEDs and may be different from CBZ and VPA. Thus far, this assumption has not been tested in a formal cognitive study. Therefore, we attempted to study the cognitive profile of TPM by comparing it with VPA in a first-line add-on design with CBZ as base- line treatment. An important starting point for our study was that the first adjunctive therapy trials with TPM used dosage in- creases of 100 to 200 nig/wk. Recently, it was demon- strated that rate of dosage increase is related to the per- centage of dropouts in adjunctive therapy 16). There- fore, the question arose regarding to what extent a more gradual introduction of TPM would improve tolerability and prevent cognitive impairment. A second starting point was that, initially, target doses up to 1000 mg were used in 12- to 16-week trials, whereas a dosage range of 200 to 400 mg/d is now considered optimal for most patients 17). METHODS The study is a multicenter, randomized, observer- blinded, parallel-group clinical trial with VPA or TPM given as first-line add-on therapy to steady-state treat- ment with CBZ. Only patients with localization-related epilepsy with partial-onset seizures were included Inter- national League Against Epilepsy International Classifi- cation of Seizures, 1981). An important consideration for the design was that large changes in seizure control dur- ing a study are known to affect cognitive function to a larger extent than drug treatment and thus may obscure the cognitive effects of such treatment 10). Therefore, patients were required to be on steady-state treatment with CBZ. The objective of the study was to compare cognitive function with efficacious doses of TPM versus VPA. Therefore, the study allowed the clinicians to ti- trate TPM and VPA to a maximum tolerated dose within the range of a minimal required daily dose 200 mg of TPM) and a maximal daily dose 400 mg of TPM, 1800 mg of VPAj. It was decided, therefore, not to blind the neurologist. All observers who administered the cogni- tive tests were blinded. The randomization was carried out by random permuted blocks, stratified by center and based on a central computer-generated randomization. The study included a baseline phase of 4 weeks during which all baseline procedures were carried out, followed by an add-on phase with two periods: titration and main- tenance. Baseline cognitive function testing was per- formed up to 2 weeks before the start of the titration period. The titration period immediately followed the baseline phase and extended for 12 weeks. The dose of TPM was titrated with dosage increments of 25 mg/wk to at least 200 mgld during the first 8 weeks. Additional individual titration was allowed up to 400 mg/d or maxi- mum tolerated dose until the 12th week using dosage increments of 50 mg/wk. A 12-week titration interval was used for VPA with dosage increments of 150 mg/wk until a maximum daily dosage of 1800 mg/d or maxi- mum tolerated dose, whichever was less, was achieved. After 8 weeks of titration, a cognitive retest was carried out to check for titration effects. The maintenance period extended for 8 weeks, during which the dose of the study medication was kept stable. At the end of this phase, the end point cognitive test was carried out. During the entire study period, the dose of the baseline medication, CBZ, was kept constant. Figure 1 shows the different proce- dures during the study. Dosage and administration CBZ, TPM, and VPA were used as open-label medi- cation, with 25- or 50-mg TPM tablets or 150-mg VPA enteric-coated gelatine capsules. Bottle numbers or blis- ter box numbers were preprinted on the study drug labels and assigned sequentially when patients qualified for the study and were randomly assigned to treatment. Statistical analysis and sample size determination In cognitive function studies, the sample size must be sufficient to power the study but at the same time avoid small effects without clinical relevance that would yield statistical significance 10,18). Therefore, the sample size was calculated to be sufficient to detect the differ- ence that has been reported in trials comparing pheno- barbitone or phenytoin with CBZ 10). The estimate for a clinically relevant difference in this study was calcu- lated using an information-processing task the Comput- erized Visual Searching Task, an adaptation of Gold- stein’s Visual Searching Task) that appeared sensitive in previous studies for assessing drug-induced mental slow- ing 1 1). Twenty-four patients per treatment group was Epilepsia Vnl 41 NO. 9 2000  TOPIRAMATE AS ADD-ON THERAPY TO CARBAMAZEPINE 1169 Baseline Add on Phase 4 w ks 8 w ks I Maintenance I Titration 4 w ks 8 w ks I I I I I I I VPA 18 tng/day or MTD TPM 400 tiig/day or MTD : TPM 200 tiig/ I iy I I tizinittturri target image)* I _____________________ _ I Day -14 7 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127 133 141 Visit 1 2 3 4 6 7 Final Neuropsychonietric ; Neuropsychometric Neuropsychometric evaluation ei al uation evaluation FIG 1 The daily dose of TPM was increased in 25-mg weekly increments during the first 8 weeks of titration. By the end of these 8 weeks the patients were to achieve the minimum target dosage of 2 mg/d. During the subsequent 4 weeks the dose of TPM was increased in 50-mg weekly increments until either the maximum target dosage of 4 mg/d or the maximum tolerated dose was achieved. expected to allow sufficiently precise estimation on this test, specifically a 95 confidence interval of length 2 seconds for the between-group mean difference in score change, assuming a SD of 1.7 seconds in each group (18). Taking into account a dropout rate of about 17 , a sample size of approximately 25 patients per group (“intent-to-treat”) was selected. This sample size powers the study sufficiently to detect statistically significant differences at the 0.05 level of a magnitude that is gen- erally reported in cognitive function studies (10). The objective of the study was to assess and compare the effects of efficacious dosages of TPM and VPA on cognitive function. The primary outcome variable, there- fore, was the calculated contrasts, i.e., the differences between TPM and VPA in change from baseline to end point and secondarily from baseline to titration. These contrasts were estimated by 95 confidence intervals based on the t distribution and pooled estimate of vari- ance. If the 95 confidence interval excludes 0, the treatment groups are statistically different with the cor- responding p < 0.05. In addition to the confidence inter- vals, p values are also reported for the null hypothesis of no difference between the treatment groups. The statis- tical analysis was based on the intent-to-treat population: all patients who were randomized to treatment, entered the add-on phase, and provided at least one cognitive function test assessment after baseline. For patients who withdrew early from the study, the last observation dur- ing the add-on phase was carried forward in the analysis. As a check on the possibility that baseline differences affected treatment comparisons, additional analyses were performed on raw scores obtained during titration and at the end of the study using analysis of covariance with the baseline value as the covariate. These analyses yielded congruent results; therefore, only the comparisons of change scores will be discussed herein. Instruments Cognitive assessments were carried out during the baseline period (up to 2 weeks before the start of the titration), after the initial 8 weeks of titration (day 57 , and at the end of the study (day 141). ll tests were administered in the morning between 9 a.m. and 12 noon to prevent bias attributable to circadian rhythms. Each retesting was carried out at exactly the same hour as the baseline test. All tests were performed in a fixed order (see list of tests below). The tests were rescheduled for another day in the same week if the patient had a seizure within 24 hours or consumed caffeine (exceeding the patient’s usual morning teakoffee-drinking habits) or an antihistamine within the previous 8 hours. Throughout the trial, seizures were recorded; vital signs were con- trolled, and clinical laboratory evaluations, physical ex- aminations, neurological examinations, and evaluations of treatment-emergent adverse events were performed (one visit during the baseline period and seven subse- quent visits during the 141 days of the trial). Throughout the study, plasma levels of CBZ were obtained to evalu- ate compliance with the baseline AED. Cognitive tests The selection of cognitive targets and tests was based on consensus meetings, e.g., the workshop on measure- ment of drug-induced cognitive impairment during the 21st International Epilepsy Congress in Sydney, Austra- lia (19). Patients were examined with the “FePsy” com- Epilepsia Vol. 41 No. 9, 2000  117 A. P. ALDENKAMP ET AL. puterized neuropsychological test battery. Test presenta- tion and response registration were controlled by a mi- crocomputer, but the test procedure was always fully managed by a test technician, who could adjust instruc- tions to the individual performance level of the patient. The tests, the test procedures, and the validation of the tests i.e., the evaluation of correlations with standard neuropsychological tests) have been described elsewhere 20-22). In addition, some traditional noncomputerized neuropsychological tests were used. All tests control for retesting effects either by presenting parallel items at retesting or by presenting items randomly to avoid any “learning” of the test. Retesting effects have been re- ported to be minimal 20-22). The tests selected are listed below outcome variable numbers are indicated in parentheses). Measures of motor speed: The Finger-Tapping Task. This measures motor speed and motor fluency for the index finger of the dominant variable 1) and the nondominant vari- able 2) hand separately in average number of taps for five consecutive trials. Simple Reaction-Time Measurement. This measures reaction time on visual a white square on the screen) stimuli that are presented at random inter- vals by the computer. These tests measure activa- tion/alertness, and a strong motor speed component is involved. Score is the reaction time in millisec- onds for the dominant variable 3 and the nondomi- nant variable 4) hand. Measures of mental speed speed of information pro- cessing) and attention: Binary Choice Reaction Test. In this test, a decision component is introduced. The patient has to react differently to a red square, presented on the left side of the screen, than to a green square, presented on the right side. Reaction time here reflects not only motor speed but also the decision-making process. Score is the reaction time in milliseconds vari- able 5). The Computerized Visual Searching Task CVST). This is an adaptation of Goldstein’s Visual Search- ing Task. A centered grid pattern has to be com- pared with 24 surrounding patterns, one of which is identical to the target pattern. The test consists of 24 trials and gives an indication of the speed of infor- mation processing and perceptual mental strategies. The score is the total average searching time in sec- onds variable 6 . Memory function: Recognition o Words and Figures. The test stimuli are presented simultaneously during a learning phase. Six words and four figures are presented with a presentation time of 1 second per item. After a delay of 2 seconds, the screen shows one of these worddfigures between distracters. The target item has to be recognized. Score is the number correct out of 24 variables 7 and 8). Rey Auditory Verbal Learning Test. This test mea- sures memory span and learning strategies. Fifteen words are presented on tape this test is not pre- sented by computer and is not part of the FePsy test system) and have to be recalled in five consecutive trials. After 20 minutes, long-term recall is tested. Score is the number correct out of 75 immediate recall; variable 9 or out of 15 delayed recall; vari- able lo). These six cognitive tests yielded 10 cognitive vari- ables variables 1 to 10). Mood and well-being To control for possible interfering effects of mood or subjective well-being, two separate tests were included: Profile o Mood States 23). A scale for state- dependent mood changes, the Profile of Mood States contains 65 adjectives e.g., “happy,” “help- less”) to which subjects can react and describe how they felt during the past week. Ratings are scored for six mood states: tension-anxiety variable l), depression-dejection variable 2), anger-hostility variable 3 , fatigue-inertia variable 4), confusion- bewilderment variable 5), and vigor-activity vari- able 6 . The scores are the raw scores; all scales but the vigor-activity scale are scored such that higher scores reflect greater mood disturbance. Aldenkamp-Baker Neurotoxicity Scale 24,25). This scale has proven reliability and validity in measur- ing patient-based subjective complaints in relation to drug treatment. Score is the number of complaints ranging from 0 to 72 variable 7). These two mood scales yielded seven variables vari- ables 1 to 7). The assessment setting in each center was carefully selected by monitors and a psychologist and was stan- dardized. Testing time was about 60 minutes, with a short break 10 minutes) in the middle. Serum samples were taken in this same interval, before testing. Patients Eligible patients were selected and included in the study using the following inclusion and exclusion crite- ria. Informed consent was obtained before any trial- related procedure was performed. The study was ap- Epilepsia, Vol. 41 No. 9 2000
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