Randomized clinical study comparing Compeed cold sore patch to acyclovir cream 5% in the treatment of herpes simplex labialis.

BACKGROUND: Hydrocolloid technology has been proven effective in treating dermal wounds. A previous study showed that a newly developed thin hydrocolloid patch [Compeed cold sore patch (CSP)] provided multiple wound-healing benefits across all stages of a herpes simplex labialis (HSL) outbreak. METHODS: An assessment of CSP efficacy and safety was conducted in an international, multicentre, assessor-blinded study, which enrolled 728 subjects with a history of recurrent HSL. Of these, 351 experienced an HSL outbreak and were randomized to use CSP (n = 179) or acyclovir cream 5% (n = 172) at the onset of symptoms until the lesion healed, for a maximum of 10 days. The primary end point was the subject's global assessment of therapy (SGAT; 0-10 scale; 0 = no response, 10 = excellent response). Multiple secondary end points included clinician-assessed healing time and subject assessment of lesion protection, noticeability and social embarrassment. RESULTS: CSP and acyclovir were highly effective (mean SGAT = 7.89 and 8.00, respectively), with no significant difference observed (P = 0.65). The difference in healing times between products was not significant (median, 7.57 days with CSP vs. 7.03 days with acyclovir, P = 0.37). Both treatments were well tolerated. CONCLUSION: CSP using hydrocolloid technology provides an efficacious and safe alternative to topical antivirals in treating HSL as a wound while affording additional immediate benefits of wound protection, discretion and relief of social embarrassment.

Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group.

We conducted a randomized double-blind comparison of three doses of the novel antiepileptic drug (AED) topiramate (200, 400, and 600 mg/day) and placebo as adjunctive therapy in patients with refractory partial onset epilepsy receiving one or two other AEDs at therapeutic concentrations. A total of 181 patients completed the 12-week baseline phase and were randomized to double-blind therapy. Median percent reductions from baseline in average monthly seizure rate, the principal efficacy evaluation, were 13% for placebo, 30% for topiramate 200 mg/day, 48% for topiramate 400 mg/day, and 45% for topiramate 600 mg/day. For the seizure rate comparison of active drug to placebo p values were: topiramate 200 mg/day, p = 0.051; topiramate 400 mg/day, p = 0.007; topiramate 600 mg/day, p < 0.001. Percent responders ( > or = 50% reduction in seizure rates) were 18% for placebo, 27% for topiramate 200 mg/day, 47% for topiramate 400 mg/day (p = 0.013), and 46% for topiramate 600 mg/day (p = 0.027). A significant (p = 0.003) reduction in secondarily generalized seizures compared with placebo treatment was also documented with topiramate. Topiramate plasma concentrations were closely related to dosage, and there were no significant interactions between topiramate and other AEDs. The minimal effective dose of topiramate in this study population was approximately 200 mg/day. Mild or moderate CNS symptoms were the primary treatment-emergent adverse events, but treatment-limiting adverse events occurred in only 9% of patients given topiramate compared with 7% given placebo. Results of this initial well-controlled study in patients indicate that topiramate is a very promising new AED.

Dezinamide for partial seizures: results of an n-of-1 design trial.

BACKGROUND: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. METHODS: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. RESULTS: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. CONCLUSIONS: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

Felbamate for partial seizures: results of a controlled clinical trial.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Evaluation of antiepileptic drug efficacy. A review of clinical trial design.

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 cross-over 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Compliance in clinical trials: impact on design, analysis and interpretation.

A positive association between compliance and clinical outcome has been observed in several randomized, controlled, clinical trials. This association, seen in the placebo-treated group as well as the active-treatment group, clarifies the possibility that data analyses incorporating estimates of protocol adherence are potentially biased. In the presence of non-compliance, or missing data from any cause, several statistical analyses may seem plausible, with none clearly superior to the others. These may include an analysis of all patients randomized, with imputed values for missing data, and an analysis restricted to protocol-adherent patients. The recommended approach is a conservative one that examines consistency among the plausible analyses. Using compliance data in trial conduct can also introduce bias into trial results by inducing differential treatment of compliers and non-compliers. This possibility arises, for instance, when adherence is affected by the randomized treatment. Non-compliance can have a substantial impact on statistical power and sample size requirements in a clinical trial. Under certain assumptions, required sample sizes are doubled with 30% non-compliance and tripled with 40% non-compliance.

Confidence intervals versus p-values for interpretation of clinical trial results: introduction.

The following three papers summarize the presentations at a Society for Clinical Trials annual meeting session on the relative merits of estimation versus testing for analysis of randomized clinical trials. By design, randomized clinical trials have internal validity. Whether they also possess quantitative external validity--generalizability of effect size to some population represented by the trial subjects--is one of the main points of disagreement among the three authors. It may be unrealistic to expect a resolution that applies across the wide variety of therapeutic areas and clinical trial goals. Extrapolation from clinical trial to clinical practice is often endorsed in connection with large trials having loose entry criteria and focusing on an objective, clearly meaningful clinical endpoint. By contrast, the relevance of estimates of effect size is less clear in the case of many clinical trials conducted in the course of drug development.

Design of an individualized fixed-dose clinical trial to test the antiepileptic efficacy of a plasma flunarizine concentration.

Flunarizine (FLN) is a potential antiepileptic drug whose pharmacokinetic properties include a long half-life (2-7 weeks) and high interpatient variability in volume of distribution and clearance. The National Institutes of Health (NIH) is sponsoring a randomized, double-masked, multicenter, parallel-group, placebo-controlled clinical trial to demonstrate the antiepileptic activity of FLN. The design is based on the premise that plasma concentrations are more strongly related to drug response than are doses. For each patient, an estimate of the concentration-time curve following a single dose of FLN is used to determine a loading dose and maintenance dosage targeted at a specified plasma FLN concentration. After an inpatient, drug-loading period, the fixed maintenance dosage (of FLN or placebo) is prescribed for the entire 24-week outpatient treatment period unless a change is required for medical reasons. If the target concentration is well chosen and approximately achieved, this design has several potential advantages: (a) A fixed-dose design is simpler and less subject to bias than a design involving dosage adjustments; (b) the drug-loading period reduces from several weeks or months to 1 week the time required to achieve the target plasma FLN concentration; (c) compared with a design in which each patient receives the same dose, the decreased variability in FLN concentrations should result in fewer patients receiving subtherapeutic doses and fewer patients requiring dose reductions, as well as increased power to detect treatment effects in a population where such effects are generally small.

Clinical trials of investigational antiepileptic drugs: monotherapy designs.

The standard designs for safety and efficacy trials of investigational antiepileptic drugs are placebo-controlled, add-on trials and active control equivalence studies. These designs, motivated by medical ethics, have serious evidential limitations. Add-on trials are frequently criticized as insensitive and difficult to interpret in the presence of drug interactions; active control equivalence studies are not probative of test drug activity. As an alternative, we describe two trial designs: a placebo-control design with inpatients who in undergoing a presurgery seizure evaluation have had all antiepileptic drugs discontinued; and an active-control design aimed at showing the test drug superior to the control treatment, thus avoiding the interpretational difficulties of no-difference outcomes. A critical feature of these new designs is the limitation of subject exposure to unacceptable treatments. This is accomplished through protocol criteria--corresponding to therapeutic failure--which both terminate a subject's trial participation and form the basis of efficacy comparisons.

Topiramate as adjunctive therapy in refractory partial epilepsy: pooled analysis of data from five double-blind, placebo-controlled trials.

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 < or = 0.01) superior to placebo in reducing total seizures by > or = 75% or by 100%. When seizure types were evaluated independently, TPM significantly (p < or = 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.

Dosage adjustments in response to monitored plasma concentrations: can unblinded staff adhere to objective criteria?

A randomized, double-blind, placebo-controlled two-period crossover trial was conducted at two centers to evaluate felbamate for treatment of partial seizures in patients receiving concomitant treatment with two standard antiepileptic drugs, phenytoin and carbamazepine. During the pilot study, an interaction was seen; felbamate administration was associated with an approximate 20% increase in plasma phenytoin concentrations. Consequently, the controlled trial was designed to account for this interaction by reducing the phenytoin dosage by approximately 20% during the felbamate treatment period and using matching placebo capsules to maintain the blind. Unblinded staff were to make additional phenytoin dosage adjustments to keep the phenytoin concentrations within 20% of the patient's baseline mean. The data suggest that knowledge of treatment assignment may have influenced decisions regarding dosage adjustments even though there were objective rules for those adjustments. At one center, phenytoin dosages were adjusted at almost twice the rate during the active treatment period as during the placebo treatment period. To avoid potential bias, it is recommended that plasma concentrations be monitored by blinded staff.

The value of the number-needed-to-treat method in antiepileptic drug trials.

PURPOSE: There is controversy between clinicians and statisticians on the appropriateness of the number needed to treat (NNT) as a summary statistic to report the effectiveness of a treatment. We examine the two viewpoints and make proposals concerning the reporting of clinical trial results. METHODS: In the context of antiepileptic treatments, we explain the two different viewpoints and illustrate the use of the odds ratio, relative risk, absolute difference, and NNT on the results of randomized clinical trials with topiramate (TPM). Special attention is paid to the use of these summary statistics in meta-analyses. Here, the NNT is the expected number of patients one would need to treat to achieve a single occurrence of a specified good outcome (e.g., 50% reduction in seizure rate) in comparison to no (or placebo) treatment. RESULTS: Although the NNT is readily interpretable in some instances, it exhibits undesirable statistical behavior in other cases. In particular, confidence intervals for the NNT may split into two intervals and extend to positive and negative infinity when treatment efficacy is not clearly established by the data. Meta-analyses cannot be sensibly conducted directly on the NNT scale. CONCLUSIONS: Although other measures, such as the odds ratio, have been more commonly used in the context of meta-analyses, clinicians prefer the NNT because it gives them a clearer clinical interpretation of the effectiveness of a (new) treatment. On the other hand, statisticians do not recognize the value of the NNT, as it has undesirable statistical properties. Some reconciliation between the two views could be achieved when the clinicians acknowledge the weak aspects of the NNT and when statisticians realize that statistical appropriateness is not the same as clinical relevance. It is suggested that the NNT be used as a secondary reporting tool not on an equal footing with the classic scales.

Prototype antiepileptic drug clinical development plan.

Antiepileptic drug (AED) development has been generally difficult owing to many factors: regulatory requirements for demonstration of efficacy and safety, subject availability, traditional trial designs, and physicians' beliefs about epilepsy and its treatment. The U.S. Food and Drug Administration (FDA) regulations require a new drug to be shown safe and effective for its intended use before it can be marketed. The unambiguous proof required is a formidable hurdle for AED development. We report a recent clinical development plan highlighting innovations in clinical trial design that have addressed these requirements, discuss alternative endpoints, and compare the results of various trial designs at various stages of development. This model clinical development plan includes trials relevant to all three clinically relevant contexts in which an AED might be used: as an adjunct to an existing regimen, as a substitution for much of an existing AED regimen, and as monotherapy.

Increasing plasma concentration tolerability study of flunarizine in comedicated epileptic patients.

Twelve patients with intractable partial seizures [4 receiving carbamazepine (CBZ), 4 phenytoin (PHT), and 4 both] entered a study of the tolerability of flunarizine (FNR) at specified plasma concentrations. After an 8-week baseline period, a single-dose pharmacokinetic study was performed for each patient to calculate a loading dose and maintenance dosage necessary to achieve a target plasma FNR concentration of 30 ng/ml. The first 8 patients received the loading dose (as divided doses) during a 1-week hospitalization and the maintenance dosage for the ensuing 8 weeks. These patients proceeded to treatment periods with target concentrations of 60 and then 120 ng/ml, using doses based on an assumed linear relation between dose and plasma concentration. The last 4 patients were studied only at the 120- ng/ml target level. Results indicated that this procedure successfully approximated target levels of 30 and 60 ng/ml, but observed concentrations in the last period exceeded the 120-ng/ml target level and continued to increase with time, often necessitating a dosage reduction owing to intolerability. Calculated doses for a given target concentration varied by a factor of 12. The most frequently reported adverse experiences were sedation and increased fatigue; reports of dizziness, headache, and lethargy were also common. Based on this study, a target concentration of at least 60 but < 120 ng/ml is recommended for a controlled clinical trial of the antiepileptic efficacy of FNR.

Pharmacokinetic and dose tolerability study of ADD 94057 in comedicated patients with partial seizures.

ADD 94057, a metabolite of fluzinamide, manufactured by the A. H. Robins Company, blocks chemically- and electrically-induced seizures in animals. The primary objective of this open add-on study was to evaluate patient tolerability of ADD 94057 at ascending target plasma concentrations. Nine subjects with medically refractory seizures were receiving phenytoin (PHT, 3), carbamazepine (CBZ, 3), or both (3). A pharmacokinetic profile after a single oral 400-mg dose of ADD 94057 was used to calculate ADD 94057 dosages. After a 4-week baseline period, patients were treated for 4 weeks with weekly ADD 94057 dosage escalations. Two patients completed the study at their assigned highest dosage level; the other patients finished the study at lower dosages. The patients receiving PHT (but not CBZ) tolerated higher plasma concentrations of ADD 94057 than did patients receiving CBZ, alone or in combination with PHT. Adverse experiences included headache, ataxia, blurred vision, diplopia, dizziness, lightheadedness, and mild confusion. Eight of nine patients had reductions in seizure frequency from baseline.