***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: We conducted a r and omized 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 r and omized 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 = to50 % 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 . NEUROLOGY 1996;46 : 1684 - We conducted a multicenter , double-blind , r and omized , parallel , placebo-controlled trial in 190 patients to evaluate the safety and efficacy of three dosages of topiramate ( 600 , 800 , and 1,000 mg/day ) as adjunctive therapy for patients with refractory partial epilepsy . During an 18-week double-blind treatment period , median percent reductions from baseline in average monthly seizure rates were 1 % for placebo , 41 % for topiramate 600 mg/day and topiramate 800 mg/day , and 38 % for topiramate 1,000 mg/day . There was a 50 % or greater reduction from baseline in seizure frequency in 9 % of patients in the placebo group and in 44 % for topiramate 600 mg/day , 40 % for topiramate 800 mg/day , and 38 % for topiramate 1,000 mg/day . No placebo patients were improved by 75 to 100 % in seizure frequency , whereas 20 % of the topiramate patients were improved to this degree . All intent-to-treat drug-placebo comparisons including seizure reduction , percent responders , and investigator and patient global evaluations significantly ( p < or = to 0.02 ) favored topiramate .  Treatment-emergent adverse events consisted mainly of neurologic symptoms commonly observed during antiepileptic drug ( AED ) therapy . Sixteen percent of patients on topiramate discontinued therapy due to adverse events . Results of this study indicate that topiramate is a highly efficacious and generally well tolerated new AED . When large groups of patients are compared , incremental efficacy in the add-on setting is not observed at topiramate dosages above 600 mg/day ; however , higher doses may prove beneficial to individual patients who tolerate them . NEUROLOGY 1996;46 : 1678 - The efficacy and safety of topiramate 400 mg/day as adjunctive therapy to traditional antieleptic drugs for partial onset seizures with or without secondary generalization were assessed in a double-blind , parallel-group , placebo-controlled trial . Forty-seven patients with at least one seizure per week during an 8 week baseline were r and omly assigned to topiramate ( N = 23 ) or placebo ( N = 24 ) double-blind treatment for a 3 week titration and an 8 week stabilization period . Median percent reduction from baseline in monthly seizure frequency during the double-blind phase was not significantly greater in the topiramate group than in the placebo group ( 41 % vs. 1 % ; P = 0.065 ) . Nevertheless , other efficacy variables evidence d statistically significant differences in favor of topiramate : a greater number of treatment responders ( > or = 50 % reduction in seizures ; 35 % vs. 8 % ; P = 0.033 ) ; better investigator ( P = 0.002 ) and patient ( P = 0.021 ) global assessment s ; and greater reductions in secondarily generalized seizures compared to placebo ( P = 0.002 ) . The most commonly reported topiramate  treatment-emergent adverse events were somnolence , fatigue , abnormal vision , weight decrease , and anxiety . Most adverse events were mild or moderate in severity . Among 7 withdrawals due to limiting adverse events , 6 were CNS-related ( in 5 topiramate-treated patients ) . Results of this trial strongly suggest that topiramate 400 mg/day is effective and well tolerated in the treatment of refractory partial epilepsy OBJECTIVE To obtain descriptive safety and efficacy data for long-term levetiracetam therapy and to allow patients benefiting from add-on levetiracetam to continue treatment until the drug was available commercially . METHODS This long-term , noncomparative , open-label , follow-up study was conducted at 36 US sites . Patients with refractory partial epileptic seizures were eligible if they had benefited from add-on levetiracetam therapy in a previous study and wished to continue treatment . The levetiracetam dose was individualized over the range of 1,000 - 4,000 mg/day . Withdrawal of concomitant AEDs to allow levetiracetam monotherapy was permitted . Patients were evaluated every 12 weeks and followed for up to 4 years . Median total seizure frequency per week was the primary efficacy variable . RESULTS A total of 280 subjects , most of whom had refractory partial seizures with or without secondary generalization , were evaluated . Most were receiving either one ( 34.6 % ) or two ( 53.2 % ) concomitant antiepileptic drugs ( AEDs ) at entry . Overall , 199 ( 71.1 % ) subjects completed the study and 81 ( 28.9 % ) withdrew prematurely , most commonly due to loss or lack of efficacy or adverse events . The median total seizure frequency per week ( 0.7 at the selection visit ) remained stable . The probability of being seizure-free during the first 12 weeks was 13.4 % and 3.7 % by week 216 . Twenty-five ( 8.9 % ) subjects received levetiracetam monotherapy for at least 100 days . Levetiracetam was safe and well tolerated ; the most common levetiracetam-related adverse events were dizziness ( 6.8 % ) , convulsion ( 5.7 % ) , and somnolence ( 5.0 % ) . CONCLUSION Efficacy and safety were maintained during long-term levetiracetam treatment of refractory partial seizures The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam , 1000 mg and 2000 mg twice daily , as add-on treatment without titration in patients with refractory epilepsy . After a 1- to 4-week baseline , 119 patients were r and omized to receive levetiracetam 2000 mg daily , 4000 mg daily , or placebo for a 24-week double-blind period , then levetiracetam 4000 mg daily in a 24-week open-label phase . Somnolence was the most common reason for discontinuation , and along with asthenia , occurred more frequently with levetiracetam than placebo . Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily ( 48.1 % [ P < 0.05 ] and 28.6 % [ NS ] , respectively ) than placebo ( 16.1 % ) . In the open-label phase , the overall responder rate was 43.0 % . Switching from placebo to levetiracetam increased the overall responder rate from 16.7 % to 44.0 % . No such increase was observed with patients initiated on levetiracetam 2000 mg daily . Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and /or generalized seizures . The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose PURPOSE We wished to evaluate adjunctive therapy for partial-onset seizures with topiramate ( TPM ) for efficacy and safety in a double-blind , placebo-controlled , r and omized , parallel-group study . METHODS Sixty out patients with epilepsy ( 47 men and 13 women , mean age 32.9 years ) were studied . All had a documented history of partial-onset seizures with or without secondarily generalized seizures . After an 8-week baseline during which patients had at least one seizure per week , 30 patients each were r and omized to TPM 300 mg twice daily ( b.i.d . ) or placebo for 12 weeks . RESULTS TPM was significantly superior to placebo , as indicated by all efficacy assessment s : greater median percent reduction from baseline in the average monthly seizure rate ( 46 vs. -12 % , p = 0.004 ) ; greater number of treatment responders ( patients with > or = 50 % reduction in seizure rate ) ( 47 vs. 10 % , p = 0.001 ) , and better investigator ( p = 0.002 ) and patient ( p = 0.010 ) global assessment s of treatment . Among TPM-treated patients , the most commonly reported adverse events ( AE ) were headache , somnolence , fatigue , dizziness , and abnormal thinking . Most AE were mild or moderate in severity . CONCLUSIONS The results of the present trial indicate that TPM 600 mg/day is effective in the treatment of refractory partial-onset seizures with or without secondarily generalized seizures Summary : Gabapentin ( GBP ) has shown antiepileptic efficacy and good tolerance in clinical trials . Much remains to be learned about its clinical use . As a participating center in the US Gabapentin Study Group , we report observations that have practical implication s for patient management . Twenty‐three patients with intractable partial‐onset seizures initiated open‐label treatment after a blinded placebo‐controlled add‐on dose efficacy study . In the titration phase , GBP and concurrent antiepileptic drugs ( AEDs ) were adjusted to achieve optimal efficacy on maximally tolerated GBP doses . Nine patients had no significant improvement in seizure control and discontinued GBP . The remaining 14 patients were observed while treated long‐term with stable‐dose GBP and concurrent AEDs . Improvement was maintained as long as patients were followed : ≤4 years . The protocol ‐allowed upper dose limit , 2,400 mg/day , was well tolerated by 16 of 23 patients , indicating that higher doses may be tolerated . GBP discontinuation did not cause rebound increases in seizure frequency . The most common adverse events ( AEs ) ( in 14 of 23 ) were similar to those induced by concurrent AEDs and responded to reduction of concurrent AEDs . Many patients reported positive psychostimulatory effects . These observations extend previous findings indicating that GBP is an effective and well‐tolerated drug for treatment of partial‐onset seizures OBJECTIVE To study the efficacy and safety of gabapentin in long-term treatment . DESIGN A 4-year follow-up study of 25 patients with visits at 3-month intervals . SETTING The patients were followed up in the outpatient unit of the University Hospital of Kuopio ( Finl and ) . PATIENTS We treated 25 patients with drug-resistant complex partial seizures and secondarily generalized seizures in an open-label long-term study , using gabapentin as an additional means of therapy after a 3-month double-blind , placebo-controlled phase . Thirteen patients showed no benefit from gabapentin ; the study medication was discontinued after 4 to 6 months of treatment . Of the 12 patients who responded enough to continue treatment , five were withdrawn due to different reasons , one because of loss of response . MAIN OUTCOME MEASURES The number of patients receiving the study drug in the follow-up and reduction of seizure frequency from baseline level as analyzed by the 
    Output:
    
Analysis based on the ITT method , led to smaller effect estimates than those reported .
FO RCTs can provide important information about long-term efficacy and tolerability of newer therapies .
Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy , an analysis based on the ITT approach more closely reflects the outcomes of the patients