Clinical Trials for Treatment of Primary Generalized Epilepsies

Transcription

1 Epilepsia, 44(Suppl. 7):44 50, 2003 Blackwell Publishing, Inc. C International League Against Epilepsy Clinical Trials for Treatment of Primary Generalized Epilepsies Edward Faught University of Alabama at Birmingham Epilepsy Center, University of Alabama School of Medicine, Birmingham, Alabama, U.S.A. Summary: Purpose: To review the current state of knowledge of the treatment of primary (idiopathic) generalized epilepsy syndromes based on the efficacy results of clinical trials, to highlight obstacles in the design of these trials, and to suggest solutions for future research. Methods: Published reports of controlled clinical trials, as well as large or significant uncontrolled trials of treatments for these syndromes, were reviewed. Trials were selected for discussion based on their importance or their illustration of design issues. Results: Only a few randomized, controlled trials of therapy for these syndromes exist. Conclusions based on this Class I data include efficacy in absence epilepsies for ethosuximide, valproate, and lamotrigine, and for eight drugs for primary generalized tonic-clonic seizures. Many commonly accepted therapeutic strategies are not based on formal data. No controlled data exist for uncommon syndromes. Conclusions: More clinical trials of therapies for primary generalized epilepsies are needed. To overcome design obstacles, better funding, multicenter cooperation, inclusion of children, study designs requiring fewer patients, equivalent-control designs, use of EEG and video seizure counting, and better syndrome identification will be required. Key Words: Clinical trials Generalized seizures Primary generalized epilepsies Idiopathic epilepsies Antiepilepsy drugs. The design and interpretation of clinical trials for primary (idiopathic, genetic) generalized epilepsies involves consideration of several problems that differ from those encountered in clinical trials for localization-related epilepsies. Research in this area encounters some unique difficulties; consequently, data from well-controlled trials of therapies for these syndromes are sparse. There are fewer trials enrolling fewer patients, and very few data from Class I studies (randomized, controlled, blinded clinical trials) are available. We will review the problems associated with this endeavor, examine selected clinical trials for illustrative purposes, assign a quality level to therapeutic conclusions in the literature, then suggest possible solutions that may lead to better data and more confident therapeutic plans. This discussion is not a comprehensive review to support evidence-based guidelines. It includes only selected studies to illustrate problems and solutions, but includes most of those containing Class I evidence for efficacy. Choice of drug based on adverse effect profiles, ease of use, cost, and other variables is important, but this review focuses only on efficacy data. Address correspondence and reprint requests to Dr. E. Faught at 312 Civitan International Research Center, University of Alabama at Birmingham, th Avenue South, Birmingham, AL 35294, U.S.A. faught@uab.edu OBSTACLES TO CLINICAL TRIALS FOR PRIMARY GENERALIZED EPILEPSIES Syndrome frequency Generalized epilepsies are less common than localization-related epilepsies, especially in the adult population. This slows recruitment, increases time and expense, and lessens economic incentives for development of new therapies. Syndrome identification In clinical trials for partial-onset seizures, the etiology and anatomy of the epilepsy syndrome are largely ignored. This should make us uneasy, since there is no a priori reason to believe that seizures caused by different things or affecting different parts of the brain will respond to the same treatments. In practice, it seems that selecting a population exhibiting the most common final expression, complex partial seizures, provides enough homogeneity to identify drug effects. We are able to consider the secondarily generalized tonic-clonic seizure for this purpose, simply as a quantitatively worse partial-onset seizure. This is not necessarily the case with the generalized epilepsies. Clearly, we cannot lump them all together in clinical trials. Most syndromes incorporate more than one seizure type, and the types are electroclinically and probably molecularly distinct. Many drugs that control generalized-onset tonic-clonic seizures worsen absences. 44

2 TRIALS FOR GENERALIZED EPILEPSIES 45 Even if we decide to focus on seizure type, not epilepsy syndrome, we are faced with genetic heterogeneity. Absence is a component of several syndromes; should we do clinical trials focusing on one seizure type or on one syndrome with several seizure types? The latter makes more sense, but how do we account for the genetic heterogeneity in a syndrome such as juvenile myoclonic epilepsy (JME)? This may very well translate into differential responses to drugs, although so far it has not made much difference. On the other hand, we still do not have a clear idea of the boundaries of the various epilepsy syndromes (1). Seizure counting Absence and myoclonic seizures are hard to count. Seizure frequency is very high in some patients. These outliers may skew parametric statistical measures. Generalized tonic-clonic seizures are easy to count, but in many patients they are infrequent, especially if the study is of new-onset patients or involves baseline drug therapy. Infrequent seizure occurrence prolongs trials and decreases statistical power. Seizure classification Many older studies of generalized tonic-clonic seizures were probably heavily contaminated by partialonset seizure disorders with secondary generalization. Even if the importance of this distinction is recognized, it is not always easy to make, especially in new-onset patients. Use of the EEG helps but does not solve this problem. Asymmetries in the EEG of patients with generalized epilepsies are not infrequent and may be overinterpreted as indicating partial-onset seizures (2,3) Conversely, secondary bilateral synchrony can lead to misclassification of frontal-onset seizures as generalized-onset. Seizure danger Convulsive seizures are usually more dangerous than simple or complex partial seizures. Therefore, a study of convulsive seizures must take into account the ethics of an endpoint requiring a certain number of such events. This conflicts directly with the goal of observing enough seizures in a given patient to conclude that there is a difference between therapies. Efficacy of available treatments Both the real (conclusively proven, Class I evidence) and assumed (generally accepted but never rigorously demonstrated) efficacy of available treatments for these syndromes inhibits further research. Seizure-free patients do not ordinarily enroll in clinical trials, nor should they. This greatly diminishes both the potential pool of participants and the economic incentive for development of this indication. Childhood predominance Most generalized epilepsies are more common in childhood. Enrollment of children in clinical trials may be approached with reluctance by parents or physicians and is subject to additional regulatory requirements. Age-related phenomenology The clinical expression of primary generalized epilepsies is heavily age-related. This is not so much a problem for short-term studies, except in infants, but might be a problem for long-term follow-up results. Seizure frequency and seizure types may evolve within the same patient, and even syndrome classification may change: 15% of a group of patients with childhood absence epilepsy eventually progressed to JME (4). Disregard for seizure type and seizure syndrome This problem is more iatrogenic than biological. The literature is replete with studies of drug X in childhood epilepsy or on new-onset seizures. The first publication format means only that the author is a pediatric neurologist, and the second reflects the difficulty in early classification. It is often difficult from such reports to tease out the effect of drug X on a particular seizure type, never mind a specific syndrome. SPECIFIC TRIALS IN PRIMARY GENERALIZED EPILEPSIES There are hardly any formal data for some of the relatively uncommon primary generalized epilepsies of early childhood, including benign neonatal familial convulsions, benign neonatal convulsions, and benign myoclonic epilepsy of infancy, as well as for syndromes that may or may not be primary, such as epilepsy with myoclonicastatic seizures and epilepsy with myoclonic absences. Most reviewers suggest that valproate (VPA) is the drug of choice (5 8) but this is based mainly on Class III evidence (case series, expert opinion). Lamotrigine (LTG) may also be helpful for epilepsy with myoclonic absences, but this syndrome seems to be less treatable than most of the others (9). We will review selected trials in two well-defined syndromes for which some more secure evidence exists: childhood absence epilepsy and JME, and for one phenomenon that at this point can best be regarded as a seizure type that may comprise or overlap with several syndromes: the primary generalized tonic-clonic seizure. There are no clinical trials focusing specifically on juvenile absence epilepsy; the consensus of opinion that VPA is the drug of choice is based on extrapolated experience from its efficacy in control of the component seizure types, with a few open-label reports (10).

3 46 E. FAUGHT Trials in childhood absence epilepsy Class I evidence VPA s efficacy in absence was demonstrated in an early double-blind parallel trial (11). Disadvantages: The method of verifying seizure counts was clinical, not prolonged EEG. Conclusion: VPA and ethosuximide (ESM) were equally effective, about 80%, for absence. A randomized, double-blind crossover trial was designed to compare the efficacy of ESM with VPA in a group of 45 children aged 4 18 (12). Advantages: The problem of seizure counting was solved by the use of EEGvideo monitoring. Disadvantages: Numbers were small: only 16 patients were naïve to drugs. Of the rest, many were on drugs that could exacerbate absence 7 on carbamazepine (CBZ), 17 on phenytoin (PHT). This study was not a true crossover: if patients were seizure free on the first drug, they were not crossed to the second. Conclusions: Both drugs were equally effective in suppressing absence seizures; some patients responded to one but not the other, and a few to neither. LTG was administered to patients with a new diagnosis of absence seizures in an enrichment design (13): all patients received open-label active drug; those who became seizure free were then randomized to continue drug or be tapered to placebo only. Advantages: The primary endpoint was seizure freedom as verified by 24-h EEG. All patients were previously untreated, and all were on monotherapy LTG. Placebo exposure was minimized. Intent-to-treat data were provided. Disadvantages: The design makes dose ranges hard to compare with parallel fixed-dose trials. Because patients were titrated to their individual best dose in the open-label phase, a median response rate at specific doses was difficult to determine. However, this may be considered an advantage of the design since it simulates routine clinical practice. The absolute initial response rate was not determined in a controlled fashion. Conclusions: On open-label initial treatment, 71% of patients became seizure free; 62% of those then randomized to LTG remained seizure free compared to only 21% of those then randomized to placebo (p = 0.02). Class II evidence An early study of VPA in 24 patients with absence demonstrated both clinical efficacy and suppression of spike-wave discharges on 6-h EEGs (14). This was an example of the many open-label series of patients reporting good efficacy of VPA for absence in the 70 90% range based on historical controls (15). In a small open-label study, the efficacy of the combination of VPA and ESM was confirmed in some patients in whom neither drug alone was satisfactory (16). An interesting approach to Class II data was the Canadian Clobazam Cooperative Study (17): practicing neurologists filled out questionnaires reporting their clinical use of clobazam (CLB) for several epilepsy syndromes, including absence. This was open-label, uncontrolled data, but a standard format was used. CLB was reported to control absence completely in 25% and to produce >50% seizure reduction in 48%. This study design has the advantages of large numbers and gives a snapshot of actual clinical practice, but endpoints are not blinded and treatment is not controlled. This procedure is also known as a large, simple trial. Class III evidence There are several small, open-label series of patients with absence treated with the newer drugs. For example, topiramate (TPM) may be useful in some patients with absence (18). Expert opinion: textbook chapters with reviews of the literature and conclusions state that VPA and ESM are drugs of choice for pure childhood absence, and that VPA is preferred for juvenile absence epilepsy because of the high probability of tonic-clonic seizures (19,20). Trials in juvenile myoclonic epilepsy Class I evidence There are no studies focusing exclusively on JME that fully meet criteria for Class I evidence, despite the common occurrence of this syndrome. Undoubtedly, many of the controlled studies of new-onset seizures contain a proportion of patients who in fact have JME, but these are not easily separable from the general category of patients with primary generalized tonic-clonic seizures. Two studies of TPM of identical design were carried out in Europe and the United States (21). The purpose was to test the efficacy of TPM for primary generalized tonicclonic seizures, but among the subjects there were enough with JME to perform a subgroup analysis (22). Six of 11 TPM-treated patients, but only 2 of 11 placebo-treated patients, had a >50% reduction in numbers of tonic-clonic seizures (p = 0.03). Since these response rates are very similar to the entire study population, one may conclude that tonic-clonic seizures respond about the same to VPA regardless of the primary generalized epilepsy of which they are a feature, or that more of the population enrolled actually had JME than were identified as such. Advantages: This was an adjunctive therapy study, reducing risk to patients. The dependent variable, the number of tonicclonic seizures, is fairly easy to count. Apparently, this was the first ever study to actually demonstrate a difference between drug and placebo treatment of primary generalized tonic-clonic seizures (22). Disadvantages: This fixed-period study, with a requirement for three convulsions during an 8-week baseline and then 20 weeks of titration and treatment, potentially exposed patients to many convulsive seizures without changes in treatment. Subgroup analysis is not ideal since it is not a prospectively designed endpoint. Myoclonus was impossible to count

4 TRIALS FOR GENERALIZED EPILEPSIES 47 from patient calendars; furthermore, the numbers of JME patients in these studies were too small to permit a conclusion about the effect of TPM on myoclonus. Conclusion: TPM was effective for primary generalized tonic-clonic seizures occurring as part of JME. No difference in control of absence, myoclonic, or tonic-clonic seizures between 1,000 and 2,000 mg daily doses of VPA could be demonstrated in a study of patients with JME (23). Furthermore, EEG and other neurophysiological studies also failed to show a dose response. This result clearly illustrates a pitfall of clinical trials of generalized epilepsies: they can be so easily treatable that a small dose of an effective medication is just as good as a large dose. If one is trying to convince the FDA to grant an indication from such a result, one will be disappointed. Advantages: This was a double-blind, randomized, crossover study. Disadvantages: The low-dose control selected was too high. (Note: The use of low-dose VPA 15 mg/kg/day as a nonequivalent control has been criticized because of the belief that that dose is a pseudoplacebo. Critics should reflect on the result of this study.) Class II evidence Even more than for childhood absence, the amount of Class II and III evidence that VPA is an effective drug for JME is overwhelming. A complete listing of all retrospective series and open-label studies would be quite long, but in summary the data suggest seizure control in 80 90% of patients (24). In a few articles in which a breakdown of VPA s effects on the common seizure types of JME is given (25), it is interesting to note that it varied little: 82 85% for absence, tonic-clonic, and myoclonic events. This characteristic of VPA cannot be extrapolated to newer drugs, where differences in efficacy between seizure types within the same syndrome are emerging. Class III evidence Evidence for efficacy of other drugs for JME is all Class III at this time. Clonazepam (CZP) suppressed myoclonus in 17 patients but did not suppress tonic-clonic seizures (26). LTG fully controlled 5 of 12 patients in whom VPA had been unsatisfactory (27). Five adolescent females with JME became seizure free with methsuximide (MSM) (28). In a chart review of 84 patients with JME, the effect of acetazolamide on tonic-clonic seizures could be isolated in 31, and in 14 it controlled them (29). Felbamate (FBM) was effective as an add-on in a few patients with JME (30). Reviews summarize the prevailing opinion that VPA and, if absence alone, ESM are drugs of choice but that newer drugs, including LTG and zonisamide (ZNS), are useful for many primary generalized epilepsies (7). Levetiracetam (LEV) and TPM may be useful in some patients (31). Trials in primary generalized tonic-clonic seizures Although there are quite a number of well-designed studies of drug effects on tonic-clonic seizures, it is difficult to move beyond seizure type to determine drug effects on specific epilepsy syndromes. The boundaries between various syndromes featuring primary generalized tonic-clonic seizures are not well-defined; the nature of this nosological problem is well-described by Fisch (32). There is probably heavy overlap between patients with JME and other syndromes involving tonic-clonic seizures in most study populations, especially the earlier ones. For example, it is impossible to derive conclusions from the literature about drug efficacy on epilepsy with grand mal seizures on awakening (EGMA). There is wild disagreement about the frequency of this syndrome, with the percentage of patients among all with primary generalized tonic-clonic seizures varying from 17 to 53% in various series (33) and, as a percentage of all patients with epilepsy, from 1.2 to 31.5% (24). Since grand mal seizures in most patients with JME have a morning predominance, and myoclonic jerks are often unreported or unobserved, many patients with EGMA may actually have JME. Until recently, most large drug-comparative studies, such as the Veterans Administration studies, have enrolled patients with either partial-onset seizures or generalized-onset tonic-clonic (i.e., primary generalized) seizures (34,35). Although no major differences have emerged, for the older drugs, between efficacy against secondarily-generalized or primary generalized tonicclonic seizures, such differences with new agents are theoretically possible given our limited knowledge of the basic mechanisms of generalization. It is well known that nearly all comparative studies involving PHT, CBZ, barbiturates, and VPA have shown equivalent efficacy against generalized tonic-clonic seizures, whether of partial or generalized onset (34 36). Class I evidence We must decide at the outset whether trials using fulldose active control treatments are acceptable for proving efficacy. If we do not, then the only randomized controlled trial of primary generalized tonic-clonic seizures using a nonequivalent control is the TPM trial (21) described previously. If we do, then we can accept data from several head-to-head drug comparisons, although much of the data come from new-onset seizure studies in which it is not always possible to know that the convulsive seizures were generalized from the outset. The Cochrane Epilepsy Group found usable data for 669 patients from five trials of PHT and VPA monotherapy and reported no clear-cut differences in efficacy, including no interaction of treatment and seizure type (37). Thus, the idea that VPA is better for generalized-onset and PHT for partial-onset seizures was neither confirmed nor refuted, at least for tonic-clonic seizures.

5 48 E. FAUGHT In a large study of 260 patients with new-onset seizures, the efficacy of LTG and CBZ was compared (38). The primary endpoint was time to first seizure on treatment. Of patients in each group with primary generalized tonicclonic seizures, 47% were fully controlled, although a secondary endpoint, dropouts due to adverse effects, was favorable to LTG. Advantages: There were sufficient numbers to examine this subgroup. Drug doses were adjusted by serum levels. There was no placebo exposure. Disadvantages: EEG data were not provided. There is the usual disadvantage of an equivalent-control study: it provides no information on natural history or on whether either treatment is superior to no treatment. New-onset seizure studies have proven remarkably insensitive to differences in drug efficacy, or perhaps none exist. This is probably because once one subtracts the large group of patients who will do well on any reasonable drug and the smaller group who will do poorly on anything, there remains only a small proportion of patients in whom a difference in drug efficacy can be demonstrated. Conclusion: CBZ and LTG were equally effective for control of primary generalized tonic-clonic seizures. In another new-onset seizure trial enrolling 249 patients, oxcarbazepine (OXC) was compared with VPA (39). Ninety-five patients had generalized-onset seizures; in all but three patients, they were tonic-clonic. No significant difference in complete control for these 95 patients was found: 72% for OXC, 62% for VPA. Advantages: This was a large study with no placebo exposure. Disadvantages: EEG data were not provided. Patients with other types of generalized-onset seizures were excluded, probably because of the perception that OXC, like CBZ, may worsen absence and myoclonus. In the real world, it may be difficult for physicians to know whether the tonicclonic seizures are part of a mixed seizure syndrome with other types of generalized seizures. Conclusion: OXC and VPA were equally effective for primary generalized tonicclonic seizure. CONCLUSIONS: THERAPY FOR PRIMARY GENERALIZED EPILEPSIES Based on Class I evidence: a. VPA, ESM, and LTG are effective for absence. b. PHT, CBZ, phenobarbital, primidone (PRM), VPA, TPM, OXC, and LTG are effective for primary generalized tonic-clonic seizures. Based on Class II evidence: a. VPA is effective for myoclonic seizures. b. CLB is effective for absence, myoclonic, and tonicclonic seizures. Based on Class III evidence: a. ZNS and CZP are effective for absence seizures. b. CZP, PRM, MSM, acetazolamide, TPM, ZNS, FBM, and LEV are effective for myoclonic seizures. DISCUSSION It is revealing to note the differences between the list of conclusions based on clinical trials and the recommendations of experts, which formally occupy a lower status in the hierarchy of evidence-based medicine (Class III). Looking at the quality of data reveals gaps in our knowledge that may highlight the shaky nature of some expert opinion. For example, there is little if any actual evidence that VPA is superior to CBZ or PHT for primary generalized tonic-clonic seizures. On the other hand, evidencebased conclusions can be simplistic, not taking into account factors other than efficacy, particularly safety and tolerability. No expert, for example, would advocate using FBM rather than VPA as first-line treatment for JME, although Class I evidence exists for neither. We also must weigh the amount as well as the quality of evidence: Do we really need randomized, controlled trials to prove to us that VPA works well for myoclonus? Class I evidence, while the gold standard, is not always essential to guide clinical practice. What studies do we need, then, and how should we design them? It is apparent that VPA is not appropriate for or well tolerated by all patients, thus we need alternatives for absence and myoclonic epilepsies. Here are examples of questions that need answers: a. Does LTG improve or worsen myoclonic seizures? b. Does TPM have any effect on absence seizures? How does it compare to VPA for myoclonus? c. What are the roles of LEV and ZNS in primary generalized epilepsies? Other questions must await better syndrome classification, based on genetic studies, with eventual correlation to basic ion channelopathies or other fundamental pathologies. Eventually, we may be able to target these abnormalities with more rational and selective pharmaceuticals. In the meantime, what can we do to overcome the obstacles listed at the beginning of this review to improve the design of studies of generalized epilepsies? Here are some suggestions: a. Persuade companies and funding sources to initiate studies. These syndromes are relatively common and have been neglected in comparison to partial-onset seizures. b. Study children earlier in new drug development. This will provide information about generalized syndromes in the group for which it is most needed. c. VPA is an acceptable standard for the efficacy comparison of new agents in all these syndromes. Activecontrol designs, using full-dose VPA as the control, should be acceptable for licensure of new agents

6 TRIALS FOR GENERALIZED EPILEPSIES 49 showing similar efficacy. There are several reasons why this paradigm is more open to question in partial-seizure studies; this topic has been debated hotly in recent years (40). d. Use prolonged EEG monitoring to study both absence and myoclonic seizures. This is expensive but necessary. Although EEG discharges are not a perfect surrogate for clinical seizures (41), the EEG is vital to supplement video observation (42). Video observation cannot be omitted, though, especially for myoclonus. Surely it is possible to develop a quantitative scale for observed myoclonus. Clinical reports from patients and families are inadequate sources of data for these seizure types. e. Consider the use of time to the Nth seizure or N of 1 designs rather than fixed time periods to study generalized tonic-clonic seizures. It is not acceptable to expose patients to more such seizures than is absolutely necessary. f. 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