Add-on Studies Research Articles

Proof of efficacy studies: endpoints

The majority of clinical trials of antiepileptic drugs (AEDs) fall into two main groups: (i) phase II and early phase III add-on studies in people with drug-resistant, chronic epilepsy, and (ii) late phase III parallel-group monotherapy studies in newly diagnosed patients. Both types of trial record the occurrence of seizures over a set period from which a large number of endpoints may be derived for analysis. Although the main objective of treatment is the suppression of seizures, other associated endpoints such as drug side-effects, quality of life, and costs are also of relevance. Within any particular trial, the required sample size will depend crucially on the characteristics of the population sampled, the type (and perhaps number) of endpoints, losses to follow-up and other deviations from protocol, as well as important statistical considerations, especially the type of design, including Type I and II error rates, and methods of analysis.

Can drugs or micronutrients prevent cataract?

Cataract is the major cause of blindness and of visual impairment worldwide, so its prevention is of the greatest importance. At present no drug therapy is licensed for use in the UK or the US, so the only treatment for cataract is by surgery, which is expensive and has adverse effects. This article reviews research on prevention of cataract by a variety of agents, including micronutrients as well as drugs. Benefits have been claimed for many compounds or mixtures and this review concentrates on those most extensively studied. Information on possible benefits of putative anticataract agents comes from a variety of approaches, from laboratory experiments, both in vitro and in vivo, to epidemiological studies in patients. Sorbitol-lowering drugs were the first to be examined systematically and progressed to clinical trials which were disappointing, and now the entire rationale for their use in prevention of cataract is questionable. Micronutrients showed little promise in animals but came to clinical trial in patients with cataract without the publication of any major benefit. Pantethine showed more promise in animal studies but the only clinical trial was abandoned early. A variety of laboratory and epidemiological evidence supports the benefits of aspirin-like drugs but there has been no trial specifically in patients with cataract. Add-on studies to trials of aspirin for other indications have not been encouraging. Research into other compounds is interesting but less advanced.

Do new antiepileptic drugs justify their expense?

HE FIELD of antiepileptic drug (AED) therapy has been an unusual one, being dominated by old drugs such as phenobarbitone (introduced in 1912) and phenytoin (introduced in 1938). Until recently drugs such as carbamazepine and valproate sodium, introduced into clinical practice in the early 1970s, were regarded as new drugs. However, in the last 7 to 8 years a number of new and potentially exciting AEDs with novel mechanisms of action have become available worldwide. After an initial inevitable burst of enthusiasm for them, we are now reaching a point where a more realistic assessment of their effectiveness can be made. Purchasers of health care, in particular, increasingly demand information to show that new and inevitably more expensive drugs do have benefits to justify the cost. Because epilepsy represents the most common of neurologic disorders, an indiscriminate switching from old to new AEDs would have considerable economic implications. This observation is confirmed in a survey undertaken in the Mersey region of the United Kingdom during 1992, which showed that although the new drugs represented only 7% of prescriptions to people with epilepsy, they represented 39% of the total drug costs that in their turn accounted for one third of direct medical costs. 1 To justify their extra costs, new AEDs will need to demonstrate greater efficacy against particular seizure types or epilepsy syndromes, better tolerability, or greater safety than existing therapies. There also may be more intangible aspects of their value that need to be taken into account in justifying their expense. EFFICACY In the modern era, new AEDs will receive regulatory approval as a result of placebo-controlled, add-on, double-blind studies, almost always in populations of patients with refractory partial epilepsies. These studies are open to considerable criticism 2 but in essence show that an individual drug, when used in combination with a number of other AEDs, is better than nothing (placebo) and is reasonably well tolerated and apparently safe. These studies do not allow consideration of comparative efficacy and tolerability, nor do they define the range of effectiveness of a drug against different s eizure t ypes a nd s yndromes. In an age when metaanalysis is becoming fashionable, it is possible to make some estimates of varying treatment effects of new AEDs from placebo-controlled studies. 3,4 There is a trend for differences in efficacy and tolerability, with drugs such as topiramate and vigabatrin appearing more effective but less well tolerated than drugs such as gabapentin and lamotrigine. However, any differences, where they exist, simply may be because the former drugs have been tested in close to and even above maximumtolerated dosage, while the latter drugs have been studied in clinical trials at doses much closer to minimal effective doses. Unfortunately, standard AEDs rarely have been studied in similar placebo-controlled add-on studies in similar populations of patients. Valproate is the exception and estimates of its efficacy do seem broadly similar to those of newer drugs. 3 Since new drugs have received licenses, more clinically informative studies have become available. Comparative studies of monotherapy against carbamazepine have been published for lamotrigine, 5,6 vigabatrin, 7,8 and gabapentin. 9 The re

Lamotrigine in Absence and Primary Generalized Epilepsies

Although lamotrigine has been approved in the United States as adjunctive therapy for partial seizures in patients older than 12 years, there is increasing evidence that it is just as effective, if not more effective, in the treatment of generalized seizures. A large number of open-label studies and some single-blind data, all using lamotrigine as add-on therapy in patients with previously refractory generalized seizures, are available. Controlled studies, some on newly diagnosed, previously untreated patients with generalized seizures are ongoing. Investigations have demonstrated that patients with the following generalized seizure types improve with lamotrigine add-on therapy: Typical and atypical absence, atonic, generalized tonic-clonic, myoclonic, and clonic seizures. Response rates, defined as the percentage of patients with better than 50% reduction in seizure frequency, have been, depending on seizure type, in the range of 30% to 56%, with 0 to 33% of the patients becoming seizure free. The best responses have been noted in typical and atypical absences, and atonic seizures. Children and adults appear to have comparable responses. In addition, add-on studies in patients with specific, previously refractory, epilepsy syndromes have demonstrated that the best improvement in seizure control occurs in patients with petit mal epilepsy, "other symptomatic" generalized epilepsies, and in Lennox-Gastaut syndrome, followed by patients with other myoclonic epilepsies, myoclonic absence and West syndrome. Many previously refractory patients are able to achieve lamotrigine monotherapy. However, patients with nonprogressive myoclonic epilepsy have little, if any, response. Early data from ambulatory encephalographic (EEG) recordings in patients with previously refractory absence seizures, and from controlled studies on patients with newly diagnosed typical absence seizures, appear to confirm the efficacy of lamotrigine in those patients. Controlled studies are ongoing in patients with absence seizures, in patients with generalized tonic-clonic seizures, and in patients with Lennox-Gastaut syndrome. Dosing in generalized seizures is similar to that for partial seizures. Because of the shorter half-life of lamotrigine in children, as compared to adults, higher (mg/kg) doses are often needed in young patients. We conclude that lamotrigine is a promising drug for absence and primary generalized seizures in both children and adults.

Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects.

We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered. We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/AToxL ratio to do so from serum levels of individual drugs. The PDD/DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/AToxL is the sum of each observed serum level divided by its average toxic level. We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al.. Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of AE is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate.

Outcome measures for the assessment of new antiepileptic drugs.

For the approval of any new medicinal product quality, safety and efficacy are essential requirements. This manuscript focuses on the clinical development programme. For the investigation of antiepileptic drugs some international guidelines are of special importance. They are based on the knowledge of many experts and can be seen as a consensus on minimal requirements; deviations must be thoroughly justified. In phases II and III, usually randomised, double-blind add-on studies versus placebo in patients with therapy-resistant seizures are used to get an impression of the efficacy and certain safety issues. A clear dose-response relationship may be a good indication for efficacy. However, assessment of safety of the new product in add-on studies is difficult. Therefore comparative phase III monotherapy studies versus established antiepileptic drugs are essential to confirm the results obtained in add-on studies and are needed for a proper judgement of the efficacy/safety balance. The percentage of reduction of seizure frequency has played a dominating role as efficacy criterium. Nowadays preference is being given to the percentage responders. Which parameter is the most relevant for the given group of patients and what change is considered clinically relevant must be thoroughly argued. The definition of responder should focus on major benefit for the patients involved.

Lamotrigine for the treatment of epilepsy in childhood

Objective: In this multicenter study, the efficacy and tolerability of lamotrigine were assessed in 285 children less than 13 years of age, recruited from 37 centers in 11 countries. Methods: Pooled data from five open add-on studies have been analyzed. All the children had treatment-resistant epilepsy and most had two or more seizure types. Seizure frequency and global evaluation were assessed at the end of four successive 12-week periods of therapy. Results: Seizure frequency was reduced by 50% or more in one third of the patients. Lamotrigine was effective in all seizure types examined, particularly for typical and atypical absence seizures. Atonic seizures also responded well. Improvement was well maintained during the treatment period. The maintenance dose had to be adjusted according to concomitant medication; dose ranges were 1 to 5 mg/kg per day for children taking valproate and 5 to 15mg/kg per day for those not taking valproate. The commonest reported adverse experiences were somnolence, rash, vomiting, and seizure exacerbations. Adverse experiences led to withdrawal of treatment from 36 patients (12.6%). Conclusions: These results indicate that lamotrigine is well tolerated and is effective for a broad range of seizure types, especially absence seizures and atonic seizures. (J P EDIATR 1995;127:991-7)

Design of clinical antiepileptic drug trials

It may fairly be claimed that up to the last decade no antiepileptic drug (AED) had undergone rigorous testing. The development programmes of the new AEDs registered in recent years have necessarily been innovative, and methods of AED testing are still undergoing rapid evolutionary change. Clinical evaluation of AEDs is both difficult and complex, due mainly to two factors: (1) intermittence of clinical events, which means that dosing for periods of several weeks is generally necessary, leading to problems of poor compliance and inaccurate reporting of events by carers and patients; and (2) therapeutic necessity, which means that it is, in general, unacceptable to withhold effective treatment from a person with epilepsy. Consequently monotherapy, either with a trial drug or with placebo, can rarely be justified. In consequence most phase II trials use add-on therapy which in turn causes various problems. Conventional phase II AED trials are usually placebo-controlled add-on studies employing either a parallel or crossover design. The latter is subject to a number of practical and theoretical objections, notably on grounds of carry-over and order effects. Increasing attention has recently been directed to ethically acceptable monotherapy designs. One approach first exploited in the development of felbamate is the performance of monotherapy trials in patients whose AEDs have been withdrawn as part of a preoperative assessment protocol. Other possibilities for achieving monotherapy are also discussed.

Vigabatrin in the management of generalized seizures in children

The interpretation of the results of the use of vigabatrin (VGB) in generalized seizures and epilepsies in children has been difficult. Most studies have assessed patients on the basis of both seizure type and epilepsy syndrome and the numbers of patients have been small. Some 'generalized' epilepsy syndromes (specifically the Lennox-Gastaut syndrome) are characterized by multiple seizure types which are frequently not analysed individually in terms of drug response. By contrast West syndrome is easier to evaluate as the spasms are the only, and characteristic, seizure type. Vigabatrin has been used as both add-on, and monotherapy in the treatment of spasms. The results of add-on studies suggest that symptomatic spasms respond best, with 40-100% of children becoming spasm-free and many others showing a reduction in seizures of over 50%. The limited, reported data on VGB-monotherapy in West syndrome have been encouraging with over 50% of patients experiencing a total and sustained control of seizures with minimal or no adverse events; however, the pattern of response (symptomatic cases responding better than cryptogenic cases), has not, as yet, been confirmed. The 'non-progressive' myoclonic epilepsies tend to be exacerbated with 25-50% of patients experiencing an increase in seizure frequency; this is an interesting observation in view of the improvement seen in infantile spasms, which are also classified as a myoclonic seizure. The use of VGB in other generalized seizures and epilepsy syndromes has been neither assessed, nor reported. This reflects the fact that these seizures/syndromes are easily and well controlled using the 'older' anti-epileptic drugs.

Sensitivity of dopamine D 2 receptors following long-term treatment with roxindole

The selective presynaptic dopamine D 2 receptor agonist roxindole was studied in specific pre- and postsynaptic models in rats to see whether it induced changes in dopamine D 2 receptor sensitivity. Following treatment with 0.3 or 3 mg/kg per day i.p. for 21 days, the reversal of γ-butyrolactone-induced striatal dihydroxyphenylalanine accumulation was unchanged as compared to that after acute treatment. The efficacy of roxindole in this model was not decreased after long-term treatment. Likewise, treatment for 19 days with up to 10 mg/kg per day i.p. failed to induce behavioral supersensitivity, i.e. potention of apomorphine-induced stereotypies. In a cotreatment paradigm with haloperidol (1 mg/kg per day p.o.), roxindole (10 mg/kg per day i.p.) did not alter the behavioral supersensitivity measured after a drug washout phase as compared to the effect of haloperidol alone; however, stereotypies were observed after termination of haloperidol but continuation of roxindole treatment. In contrast, roxindole (10 mg/kg i.p.) induced only weak stereotypies in haloperidol-sensitized rats when given after the washout phase instead of apomorphine. The results indicate that roxindole induces neither desensitization of presynaptic nor supersensitization of postsynaptic dopamine D 2 receptors. Nevertheless, in add-on clinical studies wirh neuroleptic, switching of treatment regimens should be performed gradually over several days until further experience is available.

Clinical trials of antiepileptic drugs performed in the private practice setting.

Clinical trials of antiepileptic drugs (AEDs) are usually performed only in major teaching centers, thus ignoring the very real contribution available from private practice. The relation between the consultant and the referring family physician is often much closer in private practice, allowing much earlier recruitment of de novo patients into clinical trials. Between October 1988 and February 1992, 50 subjects were entered into various clinical trials including gabapentin (both an open add-on trial and parallel-arm add-on study in generalized epilepsies), vigabatrin (placebo-controlled cross-over study in focal epilepsies), and lamotrigine (both placebo-controlled cross-over add-on studies and parallel-arm comparative monotherapy study in newly diagnosed patients with epilepsy). All these trials were coordinated in private neurologic practice in Sydney, Australia, as part of either national or international multicenter AED studies. The experience demonstrated the improved ease of recruitment and patient liaison available in the private sector. It also highlighted the very real logistic problems, such as the need for a noninstitutional-based ethics committee, the training of support staff and a modified primary information resource system. Inclusion of private practice centers in clinical trials demonstrates the potential for improved patient recruitment and administrative management, especially in studies requiring newly diagnosed patients.