Abstract
This article provides a comprehensive discussion of clinical outcome measures used in trials aimed at assessing the efficacy and safety of antiepileptic drugs. For efficacy, assessment still relies on careful documentation of changes in ictal activity as determined by seizure counts based on patients recall, direct clinical observation and (for absence seizures) EEG monitoring. In selected cases, assessment of seizure severity may also be indicated. The precise choice of outcome measures is largerly dependent upon the specific trial design. In short‐term regulatory trials, parameters such as time to nth seizure after randomization (or after achievement of target dosage) may be used as an index of antiepileptic efficacy, but the clinical relevance of such measures is questionable. In add‐on trials in refractory patients, changes in seizure counts and proportion of patients achieving 50%, 75% and 100% reduction in seizure frequency may be appropriate. For long‐term monotherapy trials in newly diagnosed patients, proportion of patients achieving prolonged remission (1‐year or longer) usually represents the most clinically meaningful efficacy outcome. Retention of patients on the allocated treatment over time is also a valuable measure, but it should be regarded as a composite endpoint because decision to continue treatment is dependent on both efficacy and tolerability. At present, there is no universally accepted method for evaluating side effects, particularly those which can not be documented objectively. Spontaneous reports of symptoms or use of specific checklists have advantages and disadvantages. Studies aimed at ensuring greater standardization in safety assesment should be encouraged, especially with respect to need of obtaining quantitative estimates, and information on both prevalence and incidence of side effects should be reported in all trials.
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References
Leber P. Hazards of inference. The active control investigation. Epilepsia 1989;30: S57–63.
Cereghino JJ. Clinical trial design for antiepileptic drugs. Ann Neurol 1992;32: 393–4.
Pledger G, Kramer LD. Clinical trials of investigational antiepileptic drugs: Monotherapy designs. Epilepsia 1991;32: 716–31.
Gram L, Schmidt D. Innovative designs of controlled clinical trials in epilepsy. Epilepsia 1993;34 (suppl 7): 1–6.
Johnson AL. Statistical aspects of the measurement of clinical care in epilepsy. In: Meinardi H, Cramer J, Baker G, Martins da Silva A, eds. Quantitative Assessment in Epilepsy Care. New York: Plenum Press, 1993: 11–28.
Perucca, E. Monotherapy with the new antiepileptic drugs: Test protocols, experience and indications. Berlin: Blackwell Wissenschaft; 1997 (in press).
Eadie, MJ. Problems in the assessment of potential antiepileptic drugs. CNS Drugs 1994;1:167–71.
Leber P. The implicit assumptions of active controlled trials (a critical examination). Control Clin Trials 1983;14: 133.
Beghi E, Perucca E. The management of epilepsy in the 1990s. Acquisitions, uncertainties and perspectives for future research. Drugs 1995;49: 680–94.
Baker GA, Smith DF, Dewey M, Morrow J, Crawford PM, Chadwick DW. The development of a seizure severity scale as an outcome measure in epilepsy. Epilepsy Res 1991;8: 244–51.
Duncan JS, Sander JWAS. The Chalfont Seizure Severity Scale. J Neurol Neurosurg Psych 1991;54: 873–6.
Cramer J., Mattson R. Quantitative approaches to seizure severity. In: Meinardi H, Cramer J, Baker G, Martins da Silva A, eds. Quantitative Assessment in Epilepsy Care. New York: Plenum Press 1993: 55–1.
O'Donoghue MF, Duncan JS, Sander JWAS. The National Hospital Seizure Severity Scale: A further development of the Chalfont Seizure Severity Scale. Epilepsia 1996;37: 563–71.
Devinsky O, Faught RE, Wilder BJ, Kanner AM, Kamin M, Kramer LD, et al. Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 1995;20: 241–6.
Sachdeo SK, Sachdeo RC, Reife RA, Lim P, Pledger G. Topiramate: double-blind trial as monotherapy. Epilepsia 1995;36 (suppl. 4): 33.
Schachter SC. Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 199;36 (suppl. 6): 2–6.
Lamoureaux L, Garofalo EA, Crockat JG, and the US Gabapentin Study Group 88/89. Gabapentin (Neurontin) monotherapy in men versus women and in patients receiving previous monotherapy versus those receiving previous poly-therapy. Epilepsia 1996;37 (suppl.4): 69.
Sachdeo R, Kramer LD, Rosenberg A, Sachdeo S. Felbamate monotherapy: Controlled trial in patients with partial onset seizures. Ann Neurol 1992;32: 386–92.
Faught E, Sachdeo RC, Remler MP, Chayasirisobhon S, Iragui-Madox VJ. Felbamate monotherapy for partial-onset seizures: An active control trial. Neurology 1993;43: 688–92.
Bourgeois B, Leppik IE, Sackellares JC, Laxer K, Lesser R. Felbamate: A double-blind controlled trial in patients under-going presurgical evaluation of partial seizures. Neurology 1993;43: 693–6.
Eslava-Cobos J. Objective measure of treatment outcome in epilepsy. Epilepsia 1996;37: 572–6.
Smith D, Baker G, Davies G, Dewey M, Chadwick D. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993;34: 312–22.
Ahmad S, Perucca E, Richens A. The effect of frusemide, mex-iletine, (+)-propranolol and three benzodiazepine drugs on interictal spike discharges in the electroencephalograms of epileptic patients. Brit J Clin Pharmacol 1977;4: 683–8.
Kasteleijn-Nolst Trenite DGA, van Emde Boas W, Groenhout CM, Meinardi H. Preliminary Assessment of the efficacy of Org 6370 in photosensitivity and provocation of myoclonic seizures. Epilepsia 1992; 33(1): 135–41.
Tartara A, Manni R, Galimberti CA, Morini R, Mumford JP, Iudice A, et al. Six-year follow-up study on the efficacy and safety of vigabatrin in patients with epilepsy. Acta Neurol Scand 1992;86: 247–51.
Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. New Engl J Med 1985;313: 145–51.
Dam M, Ekberg R, Lovning Y, Waltimo O, Jacobsen K. A double-blind study comparing oxcarbazepine and carbamaze-pine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;3: 70–7.
Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. New Engl J Med 1992;327: 765–71.
Richens A, Davidson DLW, Cartlidge NEF, Easter DJ. A multi-centre trial of sodium valproate and carbamazepine in adult-onset epilepsy. J Neurol Neurosurg Psych 1994;57: 682–7.
Steiner TJ. Comparison of lamotrigine and phenytoin mono-therapy in newly diagnosed epilepsy. Epilepsia 1994;35 (suppl. 8): 31.
Heller AJ, Chesterman P, Elwes RDC, Crawford P, Chadwick D, Johnson AL, et al. Phenobarbitone, phenytoin, carbamaze-pine, or sodium valproate for newly diagnosed adult epilepsy: A randomised comparative monotherapy trial. J Neurol Neurosurg Psych 1995;58: 44–50.
Verity CM, Hosking G, Easter DJ (on behalf of The Pediatric EPITEG Collaborative Group). A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. Dev Med Child Neurol 1995;37: 97–108.
De Silva M, MacArdle B, McGowan M, Hughes E, Stewart J, Neville BGR, et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347: 709–13.
Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epileps. Lancet 1995;345: 476–9.
Kalviainen R, Aikia M, Saukkonen AM, Mervaala E, Riekkinen PJ. Vigabatrin versus carbamazepine monotherapy in patients with newly diagnosed epilepsy: A randomized controlled study. Arch Neurol 1995;52: 989–96.
Reunanen M, Dam M, Yuen AWC. A randomized open multi-centre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilesy. Epilepsy Res. 1996;23: 149–55.
Chadwick DW, Roi L, Kennedy KM. Vigabatrin (Sabril) as first-line monotherapy in newly diagnosed epilepsy: A double-blind comparison with carbamazepine. Epilepsia 1996;37 (suppl 4): 6.
Mattson RH, Cramer JA. Quantitative assessment of adverse drug effects. In: Meinardi H, Cramer JA, Baker GA, Da Silva AM, eds. Quantitative Assessment of Epilepsy Care. New York: Plenum Press, 1993: 123–35.
Aldenkamp AP, Baker G, Pieters MSM, Schoemaker HC, Cohen AF, Schwabe S. The Neurotoxicity Scale: The validity of a patient-based scale, assessing neurotoxicity. Epilepsy Res 1995;20: 229–39.
Baker GA, Jacoby A, Francis P, Middleton A, Defalla B, Young C. The development of a patient-based adverse drug event profile as an outcome measure in epilepsy. (in press)
Cramer JA, Smith DB, Mattson RH, Delgado AV, Collins JF and the VA Epilepsy Cooperative Study No. 118 Group. A method of quantification for the evaluation of antiepileptic drug therapy. Neurology 1983;33 (suppl 1): 26–37.
Lammers MW, Hekster YA, Keyser A, Meinardi H, Renier WO, Van Lier H. Monotherapy or polytherapy for epilepsy revisited: A quantitative assessment. Epilepsia 1995;36: 440–6.
Louik C, Lacouture PG, Mitchell, AA, Kauffman R, Lovejoy FH, Yaffe SJ, et al. A study of adverse drug reactions algorithms in a drug surveillance program. Clin Pharmacol Ther 1985;38: 183–7.
Vickry BG, Hays RD, Engel J. Outcome assessment for epilepsy surgery: The impact of measuring health-related quality of life. Ann Neurol 1995;37: 158–66.
Cramer JA, Perrine K, Devinsky O, Meador K. A brief questionnaire to screen for quality of life in epilepsy. Epilepsia 1996;37: 577–82.
Cramer JA. Assessment of health-related quality of life in epilepsy. Pharmacy World Sci 1997;19.
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Perucca, E. Evaluation of drug treatment outcome in epilepsy: a clinical perspectiv. Pharm World Sci 19, 217–222 (1997). https://doi.org/10.1023/A:1008698807530
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DOI: https://doi.org/10.1023/A:1008698807530