Innovative Designs of Controlled Clinical Trials in Epilepsy

Summary: Uncontrolled noncomparative clinical observations of investigational antiepileptic drugs (AEDs) often lead to overoptimistic efficacy results and are therefore of very limited value for clinical AED development. The classic add-on trial with placebo as control treatment, in contrast, has provided unequivocal evidence of the efficacy of classic and new AEDs and has also identified less useful AEDs. Drug interactions, carryover effects, difficulty in analyzing individual drug action, and the recognition that monotherapy is by far the more common way of prescribing AEDs have led to the development of classic active control monotherapy trials. A major problem of these trials is a no-difference outcome, which allows no useful interpretation. Recently, two alternative monotherapy designs have been developed to avoid the deadlock of a no-difference outcome. In these designs the active control drug is administered in an attenuated form (low dosage or low concentration) or a placebo control is used when standard treatment is discontinued during presurgical evaluation. Both designs have produced unequivocal evidence of the efficacy of the investigational AED during monotherapy. Ethical concerns are minimized by the introduction of preset escape criteria for patient protection. These designs are valuable new supplements for the clinical development of investigational AEDs for monotherapy in epilepsy. In our opinion, alternative monotherapy designs should be preceded by more than one pivotal add-on, placebo-controlled trial.     

Controlled and Comparative Trials with Valproate: United States

Valproic acid (VPA) was released for general use in the United States in 1978. Since that time the use of VPA has steadily grown, and considerable literature on valproate from the United States has resulted. Despite this fact, however, very few studies that were either well controlled or compared the efficacy of VPA with that of another standard anticonvulsant drug have been published from this country.     

Neuropsychological Outcomes in Randomized Controlled Trials of Antiepileptic Drugs: A Systematic Review of Methodology and Reporting Standards

Summary: Purpose: To systematically review the methodology and use of neuropsychological tests in randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) in patients with epilepsy.
Methods: Trial reports were found by searching Medline 1966–1996 and searching through journals by hand. Inclusion and exclusion criteria were applied, and methodological and neuropsychological test data was extracted by using a pro-forma.
Results: 43 reports met our inclusion criteria, representing 40 RCTs, as three RCTs had generated two reports. Twenty-two were actively controlled, and 18 were placebo-controlled studies. Reporting of basic methods such as randomization method was poor. There has been no uniform approach to the use of neuropsychological tests, and a total of 87 has been used. The Stroop Colour Word Test and the Finger Tapping Test were most commonly used, at 13 times each, but were not used or reported in a uniform manner.
Conclusions: Poor reporting of methods and the use of a plethora of neuropsychological tests create great difficulties for anyone wishing to make sense of currently available data. If we are better to understand the neuropsychological effects of AEDs, a more rational approach is needed, for which recommendations are made.     

Double-Blind, Placebo-Controlled, Lamotrigine in Treatment-Resistant Generalised Epilepsy

Summary: Purpose : Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatmentresistant generalised epilepsy.
Methods: The study consisted of 2 × 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG.
Results: Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 250% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had 250% seizure reduction and five (25%) were seizure free.
Conclusions: This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.     

Progabide: A Controlled Trial in Partial Epilepsy

Progabide (SL 76002) was studied in a randomized double-blind crossover trial using 20 outpatients suffering from partial complex seizures. Progabide was added to the concomitant antiepileptic treatment in a fixed dosage schedule. The design included an open therapy control unit. No significant difference was established between the number of partial seizures during treatment with progabide and placebo. A trend was observed for lower seizure frequency of secondary generalized seizures during treatment with progabide. Only mild and transient side effects were observed. There was no difference between the side effects of progabide and placebo.     

Controlled and Comparative Trials of Valproate Performed in Europe and Asia

Scientifically sound investigation of new drug treatments necessitates the use of controlled designs, including random allocation and some kind of blind principle. Although this basic idea was conceived and applied, for the first time, more than a century ago, the trend of events has been tardy within all areas of medicine.     

Topiramate as Adjunctive Therapy in Refractory Partial Epilepsy: Pooled Analysis of Data from Five Double-Blind, Placebo-Controlled Trials

Summary: A pooled analysis of data from five similarly designed double-blind, placebo-controlled trials of topiramate (TPM) as add-on therapy in patients with partial epilepsy was performed. The pooled analysis allowed evaluation of efficacy end points and response to treatment for a number of study subgroups not statistically evaluable in the individual study analyses due to limited sample sizes. The five trials included 534 patients, 360 who received TPM at target dosages of 200-1,000 mg daily and 174 who received placebo. In the intent-to-treat pooled analysis, TPM was significantly ( p ≤ 0.01) superior to placebo in reducing total seizures by ≥ 75% or by 100%. When seizure types were evaluated independently, TPM significantly ( p ≤ 0.001) reduced the frequency of simple partial, complex partial, and secondarily generalized seizures. TPM was significantly ( p ≤ 0.001) better than placebo regardless of gender, patient age, baseline seizure rate, and concomitant AEDs. The efficacy of TPM in partial epilepsy is consistent across efficacy end points and across strata defined by study population characteristics.     

Efficacy and Safety of Antiepileptic Drugs: A Review of Controlled Trials

Summary: Twenty randomized, double-blind, controlled clinical trials of antiepileptic drugs (AEDs) in mostly adult patients with mostly partial onset and/or generalized tonic-clonic seizures have been reported, with a total of 1,336 patients. None of these studies has demonstrated significant differences in antiepileptic efficacy between available antiepileptic drugs, but the results show that there are considerable individual differences between patients' responses to the same drug. While side effects are common with all of the antiepileptic drugs currently available, these are usually mild and reversible. Although some toxic effects may occur more frequently with certain drugs, there is sufficient overlap between the effects of various antiepileptic drugs that most side effects cannot be attributed with certainty to any one drug. Since side effects are generally dose-related, they can frequently be avoided or minimized by careful dosage titration and individualization of therapy.