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Evaluation of Antiepileptic Drug Efficacy

A Review of Clinical Trial Design

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Summary

Up to 30% of patients with epilepsy are not adequately treated with currently available antiepileptic drugs. Despite a need for new agents, few were developed after valproic acid (sodium valproate), which appeared in the 1970s. This picture has changed recently. A number of new antiepileptic drugs have been approved for marketing, and additional approvals are expected soon. The evidence in the form of adequate and well controlled studies supporting the efficacy of each of these new drugs has included (and in some cases been wholly composed of) placebo-controlled add-on trials, showing the viability of that design.

Add-on trials, which compare a new drug with placebo in the presence of a stable regimen of antiepileptic drug therapy, can be conducted as parallel or crossover designs. These designs have been considered insensitive because they are conducted in patients refractory to available antiepileptic drugs, but add-on trials have proved able to identify effective new drugs. They also permit long term evaluation and provide information, including drug interaction data, in one of the major clinical contexts where a new antiepileptic drug may be used.

New designs now allow the evaluation of antiepileptic effectiveness in other clinical contexts, including monotherapy, and provide alternatives when drug interactions obscure add-on trial interpretation. The key feature of this class of monotherapy designs is basing patients’ trial duration on their seizure activity rather than on a fixed time period. This is accomplished by defining ‘therapeutic failure’ criteria which serve to assess efficacy of the test agent while protecting patient safety. It is hoped that investigators will continue to seek innovative designs to yield information to guide the clinical use of these new antiepileptic drugs.

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References

  1. Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. New York: Demos Pub, 1990

    Google Scholar 

  2. Schmidt D, Morselli PL. Intractable epilepsy: experimental and clinical aspects. New York: Raven Press, 1986

    Google Scholar 

  3. Group for the Evaluation of Cinromide in the Lennox-Gastaut Syndrome. Double-blind, placebo-controlled evaluation of cinromide in patients with the Lennox-Gastaut Syndrome. Epilepsia 1989; 30: 422–9

    Article  Google Scholar 

  4. MRC Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337: 1175–80

    Google Scholar 

  5. Mouritzen-Dam A. Hippocampal neuron loss in epilepsy and after experimental seizures. Acta Neurol Scand 1982; 66: 601–42

    Article  Google Scholar 

  6. Cavazos JE, Sutula TP. Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber reorganization and hippocampal sclerosis. Epilepsia 1989; 30: 702

    Google Scholar 

  7. Sutula T, Cascino G, Carazos J, et al. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 1989; 26: 321–30

    Article  PubMed  CAS  Google Scholar 

  8. Pledger GW. Carbamazepine for first seizure. Neurology 1989; 39: 1645

    Article  PubMed  CAS  Google Scholar 

  9. Rodin EA, Rim CS, Rennick PM. The effect of carbamazepine on patients with psychomotor epilepsy: results of a double-blind study. Epilepsia 1974; 15: 547–61

    Article  PubMed  CAS  Google Scholar 

  10. Richens A, Ahmad C. Controlled trial of sodium valproate in severe epilepsy. BMJ 1975; 4: 255–6

    Article  PubMed  CAS  Google Scholar 

  11. Gram L, Flachs J, Wurtz-Jorensen A, et al. Sodium valproate, serum levels and clinical effect in epilepsy: A controlled study. Epilepsia 1979; 20: 303–12

    Article  PubMed  CAS  Google Scholar 

  12. Rimmer E, Richens A. Double-blind study of gamma-vinyl-GABA in patients with refractory epilepsy. Lancet 1984; 1: 189–90

    Article  PubMed  CAS  Google Scholar 

  13. Gram L, Klosterskov P, Dam M. Gamma-vinyl GAB A: a double-blind placebo-controlled trial in partial epilepsy. Ann Neurol 1985; 17: 262–6

    Article  PubMed  CAS  Google Scholar 

  14. Tassinari CA, Michelucci R, Ambrosetto G, et al. Double-blind study of vigabatrin in the treatment of drug resistant epilepsy. Arch Neurol 1987; 44: 907–10

    Article  PubMed  CAS  Google Scholar 

  15. Jawad S, Richens A, Goodwin G, et al. Controlled trial of lamotrigine (lamictal) for refractory partial seizures. Epilepsia 1989; 30: 356–63

    Article  PubMed  CAS  Google Scholar 

  16. Schmidt D, Ried S, Rapp P. Add-on treatment with lamotrigine for intractable partial epilepsy: a placebo-controlled crossover trial. Epilepsia 1993; 34 Suppl. 2: 66

    Google Scholar 

  17. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990; 335: 1114–7

    Article  Google Scholar 

  18. Leppik IE, Dreifuss FE, Pledger GW, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991; 41: 1785–9

    Article  PubMed  CAS  Google Scholar 

  19. Felbamate Study Group in Lennox-Gastaut Syndrome. Ritter F, Dreifuss FE, Sackellares JC, et al. Efficacy of felbamate in childhood epileptic encephalopathy. N Eng J Med 1993; 328: 29–33

    Article  Google Scholar 

  20. Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993; 15: 67–73

    Article  PubMed  CAS  Google Scholar 

  21. Ben-Menachem E. Double-blind placebo-controlled trial of topiramate as add-on therapy for the treatment of complex partial seizures. Epilepsia 1992; 33: 105

    Google Scholar 

  22. Fincham R, Schottelius D, Faught E, et al. Efficacy and safety of topiramate (TPM) as adjunctive therapy in adults with refractory partial epilepsy. Neurology 1992; 42: 311

    Article  Google Scholar 

  23. Schmidt D, Utech K. Progabide for refractory partial epilepsy: a controlled add-on trial. Neurology 1986; 36: 217–21

    Article  PubMed  CAS  Google Scholar 

  24. Leppik IE, Dreifuss FE, Porter R, et al. A controlled study of progabide in partial seizures: methodology and results. Neurology 1987; 37: 963–8

    Article  PubMed  CAS  Google Scholar 

  25. Gram L, Schmidt D. Innovative designs of controlled clinical trials in epilepsy. Epilepsia 1993; 7 Suppl.: S1–S6

    Article  Google Scholar 

  26. Perucca E, Hebdige S, Frigo GM, et al. Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects. Clin Pharmacol Ther 1980; 28: 779–89

    Article  PubMed  CAS  Google Scholar 

  27. Perucca E, Hedges A, Makki KA, et al. A comparative study of the enzyme inducing properties of anticonvulsant drugs in epileptic patients. J Clin Pharmacol 1984; 18: 401–10

    CAS  Google Scholar 

  28. Ried S, Schmidt D. Vigabatrintherapie bei pharmakoresistenten fokalen epilepsien-eigene klinische Erfahrungen. Aktuel Neurol 1992; 19: 541–5

    Article  Google Scholar 

  29. Wilensky AJ, Moretti-Ojecmann L, Temkin NR, et al. Clorazepate and phenobarbital as antiepileptic drugs: a double-blind study. Neurology 1981; 31: 1271–6

    Article  PubMed  CAS  Google Scholar 

  30. Reinikainen KJ, Keranen T, Komulainen H, et al. Comparison of oxcarbazepine and carbamazepine: a double-blind study. Epilepsy Res 1987; 1: 284–9

    Article  PubMed  CAS  Google Scholar 

  31. Dam M, Ekberg R, Loyning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989; 3: 70–6

    Article  PubMed  CAS  Google Scholar 

  32. Martinez-Lage JM, Bossi L, Morales G, et al. Progabide treatment in severe epilepsy: a double-blind cross-over trial versus placebo. Epilepsia 1984; 25: 586–93

    Article  PubMed  CAS  Google Scholar 

  33. Theodore WH, Raubertas RF, Porter RJ, et al. Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991; 32: 392–7

    Article  PubMed  CAS  Google Scholar 

  34. Fuerst RH, Graves NM, Leppik IE, et al. Felbamate increases phenytoin but decreases carbamazepine concentrations. Epilepsia 1988; 29: 488–91

    Article  PubMed  CAS  Google Scholar 

  35. Graves NM, Holmes GB, Fuerst RH, et al. Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30: 225–9

    Article  PubMed  CAS  Google Scholar 

  36. Sheridan PH, Ashworth M, Milne K, et al. Open pilot study of felbamate in partial seizures. Epilepsia 1986; 27: 649

    Google Scholar 

  37. Gram L, Wulff K, Rasmussen KE, et al. Valproate sodium: a controlled clinical trial including monitoring of serum levels. Epilepsia 1977; 18: 141–8

    Article  PubMed  CAS  Google Scholar 

  38. Commission on Antiepileptic Drugs: Guidelines for clinical evaluation of antiepileptic drugs. Epilepsia 1989; 30: 400–408

    Google Scholar 

  39. Pledger GW. Drug interactions in clinical trials: Statistical considerations. In: Antiepileptic drug interactions. Pitlick W, editor. New York: Demos, 1989: 143–56

    Google Scholar 

  40. Temkin NR, Wilensky AJ. New AEDs: are the compounds or the studies ineffective? Epilepsia 1986; 27: 644–5

    Google Scholar 

  41. Schmidt D. Two antiepileptic drugs for intractable epilepsy with complex partial seizures. J Neurol Neurosurg Psychiatry 1982; 45: 1119–24

    Article  PubMed  CAS  Google Scholar 

  42. Chadwick D, Richens A, Duncan J, et al. Tiagabine HCl: safety and efficacy as adjunctive treatment for complex partial seizures. Epilepsia 1991; 32 Suppl. 3: 20

    Google Scholar 

  43. Chadwick D, Richens A, Duncan J, et al. Tiagabine HC1: safety and efficacy as adjunctive treatment for complex partial seizures. Epilepsia 1992; 33 Suppl. 3: 119

    Google Scholar 

  44. Hills M, Armitage P. The two period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7–20

    Article  PubMed  CAS  Google Scholar 

  45. Fröscher W, Bülau P, Burr H, et al. Double-blind placebo-controlled trial with flunarizine in therapy-resistant epileptic patients. Clin Neuropharmacol 1988; 11: 232–40

    Article  PubMed  Google Scholar 

  46. Shofer JB, Temkin NR. Comparison of alternative outcome measures for antiepileptic drug trials. Arch Neurol 1986; 43(9): 877–81

    Article  PubMed  CAS  Google Scholar 

  47. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985; 313: 145–51

    Article  PubMed  CAS  Google Scholar 

  48. 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. N Engl J Med 1992; 327: 765–71

    Article  PubMed  CAS  Google Scholar 

  49. Pledger GW, Sahlroot JT. Alternative analyses for antiepileptic drug trials. In: French JA, Dichter MA, Leppik IE, editors. New antiepileptic drug development: preclinical and clinical aspects. Amsterdam: Elsevier Science, 1993: 167–74

    Google Scholar 

  50. Baker G, Smith D, Dewey M, et al. The development of a seizure severity scale as an outcome measure in epilepsy. Epilepsy Res 1991; 8(3): 245–51

    Article  PubMed  CAS  Google Scholar 

  51. Smith D, Baker G, Davies G, et al. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993; 34(2): 312–22

    Article  PubMed  CAS  Google Scholar 

  52. Bourgeois B, Leppik IE, Sackellares JC, et al. Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures. Neurology 1993; 43: 693–96

    Article  PubMed  CAS  Google Scholar 

  53. Devinsky O, Faught E, Wilder B, et al. Felbamate monotherapy trial in patients undergoing surgical evaluation of partial seizures. Epilepsia 1993; 34 Suppl. 6: 69

    Google Scholar 

  54. Wulf MH. The barbiturate withdrawal syndrome. Elec-troencephalogr Clin Neurophysiol 1959; 14 (Suppl.): 1–173

    Google Scholar 

  55. Marciani MG, Gotman J, Andermann F, et al. Patterns of seizure activation following withdrawal of antiepileptic medication. Neurology 1985; 35: 1537–43

    Article  PubMed  CAS  Google Scholar 

  56. Theodore WH, Porter RJ, Raubertas RF. Scizures during barbiturate withdrawal: relation to blood level. Ann Neurol 1987; 22: 644–7

    Article  PubMed  CAS  Google Scholar 

  57. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Goodman AG, Gilman LS, Rail TW, editors. The Pharmacological basis of therapeutics. New York: MacMillan Publishing Company, 1985: 387–445

    Google Scholar 

  58. Wilensky AJ. Antiepileptic drug trials - are present methodologies satisfactory? Epilepsia 1990; 31: 645–6

    Google Scholar 

  59. Temple R. Government viewpoint of clinical trials. Drug Inform J 1982; 1: 10–7

    Google Scholar 

  60. Leber P. The implicit assumptions of active control trials (a critical examination). Control Clin Trials 1983; 14: 133

    Google Scholar 

  61. Leber P. Hazards of inference; the active control investigation. Epilepsia 1989; 30 Suppl. 1: S57–S63

    Article  PubMed  Google Scholar 

  62. Katz R. Perspective of the Food and Drug Administration. In: Porter RJ, Schoenberg BS, editors. Controlled clinical trials in neurologic disease. Boston: Kluwer Academic Publishers 1990: 85–96

    Chapter  Google Scholar 

  63. Makuch R, Pledger G, Johnson M, et al. Active control, equivalence studies. In: Peace KE, editor. Statistical issues in drug research and development. New York: Marcel Dekker, 1990: 225–62

    Google Scholar 

  64. Senn S. Falsificationism and clinical trials. Stat Med 1992; 10: 1679–92

    Article  Google Scholar 

  65. Senn S. Inherent difficulties with active control equivalence studies. Stat Med 1993; 12: 2367–75

    Article  PubMed  CAS  Google Scholar 

  66. Bromfield EB, Dambrosia J, Devinsky O, et al. Phenytoin withdrawal and seizure frequency. Neurology 1988; 39: 905–9

    Article  Google Scholar 

  67. So N, Gotman J. Changes in seizure activity following anticon-vulsant drug withdrawal. Neurology 1990; 40: 407–13

    Article  PubMed  CAS  Google Scholar 

  68. Bourgeois B, Luders H, Morris H, et al. Rapid change-over to carbamazepine monotherapy using single-dose pharmacokinetics. Epilepsia 1989; 30: 662

    Google Scholar 

  69. Dietz M, Hoeppner TJ, Bergen D. Time of occurrence of seizures associated with drug withdrawal during intensive monitoring. Epilepsia 1989; 30: 679

    Google Scholar 

  70. Faught RE, Sachdeo RC, Remler M, et al. Felbamate monotherapy for partial onset seizures: an active control trial. Neurology 1993; 43: 688–92

    Article  PubMed  CAS  Google Scholar 

  71. Sachdeo RC, Kramer LD, Rosenberg A, et al. Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol 1992; 32: 386–92

    Article  PubMed  CAS  Google Scholar 

  72. Pledger GW, Kramer LD. Clinical trials of investigational anti-epileptic drugs: monotherapy designs. Epilepsia 1991; 32: 716–21

    Article  PubMed  CAS  Google Scholar 

  73. Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: John Wiley, 1980

    Google Scholar 

  74. Friedman LN, Furberg CD, DeMets DL. Fundamentals of clinical trials. Boston: John Wright-PSG, 1981: 156–65

    Google Scholar 

  75. Woodbury DM, Penry JK, Pippenger CE, editors. Antiepileptic drugs, 2nd Ed. New York: Raven Press, 1982

    Google Scholar 

  76. Schmidt D, Jacob R. Clinical and laboratory monitoring of anti-epileptic medication. In: Wyllie E, editor. The Treatment of epilepsy. Philadelphia: Lea and Febiger, 1993: 798–809

    Google Scholar 

  77. Sanathanan LP, Peck CC. The randomized concentration-controlled trial: an evaluation of its sample size efficiency. Control Clin Trials 1991; 12: 780–94

    Article  PubMed  CAS  Google Scholar 

  78. Binnie C, Debets R, Engelsman M, et al. Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Res 1989; 4(3): 222–9

    Article  PubMed  CAS  Google Scholar 

  79. Pledger GW, Treiman DM. Design of an individualized fixed-dose clinical trial to test the antiepileptic efficacy of a plasma flunarizine concentration. Control Clin Trials 1991; 12: 768–79

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biostatistics and Research Data Services, RW Johnson Pharmaceutical Research Institute, Route 202, PO Box 300, Raritan, New Jersey, 08869-0602, USA

    Gordon W. Pledger

  2. Epilepsy Research Group, Berlin, Germany

    Dieter Schmidt

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  1. Gordon W. Pledger
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  2. Dieter Schmidt
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Pledger, G.W., Schmidt, D. Evaluation of Antiepileptic Drug Efficacy. Drugs 48, 498–509 (1994). https://doi.org/10.2165/00003495-199448040-00002

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