ucb-34714 and Fatigue

The objective of this analysis was to provide a comprehensive analysis of safety data for adjunctive brivaracetam (BRV), an antiepileptic drug (AED) of the racetam class, for treatment of focal seizures in patients with epilepsy.. Data were pooled from two phase II, placebo-controlled, double-blind, dose-ranging trials (N01114 [ClinicalTrials.gov: NCT00175929], N01193 [NCT00175825]) and three phase III, placebo-controlled, double-blind, 12-week trials (N01252 [NCT00490035], N01253 [NCT00464269], and N01358 [NCT01261325]) in patients aged ≥16 years with focal seizures, as well as a phase III, placebo-controlled, double-blind, 16-week trial in patients aged ≥16 years with focal or generalized epilepsy (N01254 [NCT00504881]). Data are presented for the approved therapeutic dose range of 50-200 mg/day. Data for BRV administered intravenously (25-150 mg doses) were pooled separately from one phase III trial (N01258 NCT01405508]) and two clinical pharmacology trials (N01256 [Part B] [UCB Pharma, data on file]; EP0007 [NCT01796899]). Adverse events (AEs) of interest were summarized in relevant categories.. The safety pool comprised 1957 patients: 1271 receiving adjunctive BRV and 686 receiving placebo. Overall, the incidence of treatment-emergent adverse events (TEAEs) was 66.9% with BRV versus 62.8% with placebo. The most frequently reported TEAEs with BRV (≥5% of patients) versus placebo were somnolence (13.3% vs. 7.9%), headache (10.5% vs. 11.5%), dizziness (10.0% vs. 7.0%), and fatigue (8.2% vs. 4.2%). Incidence of psychiatric disorder-related TEAEs was 11.3% with BRV versus 8.2% with placebo. Behavioral disorder-related TEAE incidence was low (4.0% with BRV vs. 2.5% with placebo). Irritability was reported in 2.7% of BRV-treated patients vs. 1.5% of patients receiving placebo; anger, aggression, and agitation were each reported by ≤1% of patients receiving BRV. Treatment-emergent adverse events potentially associated with psychosis were psychotic disorder (three patients on BRV vs. two patients on placebo), auditory hallucination, illusion, visual hallucination (one patient each on BRV), epileptic psychosis, and hallucination (one patient each on placebo). No additional safety concerns were identified in patients with intravenous (IV) BRV administration (n = 104).. These safety data for adjunctive BRV support its acceptable safety and tolerability profile.

Topics: Administration, Intravenous; Anticonvulsants; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dizziness; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Fatigue; Humans; Pyrrolidinones; Treatment Outcome

Brivaracetam is the latest antiepileptic drug to be approved for adjunctive therapy in focal epilepsy and has a high affinity as a SV2A ligand. The aim of this review article is to summarize the data from the pivotal studies in which more than 2000 patients received brivaracetam. A significant median reduction in seizures from 30.5 % to 53.1 % for 50 mg/day, from 32.5 % to 37.2 % for 100 mg/day and 35.6 % for 200 mg/day could be demonstrated. Overall brivaracetam appears to be well-tolerated, with fatigue, dizziness and somnolence being the main adverse side effects. An immediate change from levetiracetam to brivaracetam at a conversion ratio of 10:1 to 15:1 seems feasible and could alleviate behavioral side effects related to treatment with levetiracetam. A swift permeability into brain tissue and a faster onset of action compared to levetiracetam suggest that brivaracetam could be useful in emergency situations.

Topics: Anticonvulsants; Chemotherapy, Adjuvant; Disorders of Excessive Somnolence; Dizziness; Dose-Response Relationship, Drug; Epilepsies, Partial; Evidence-Based Medicine; Fatigue; Humans; Pyrrolidinones; Treatment Outcome

This meta-analysis systematically assessed the efficacy and safety of different doses of brivaracetam (BRV) compared with placebo as adjunctive therapy for adults with partial-onset epilepsy.. Electronic and clinical trials databases were searched for randomized controlled trials of BRV published up to May 2015. We assessed the risk of bias of the included studies using the Cochrane Risk of Bias tool. The outcomes of interest included 50% responder rates, seizure freedom, the incidence of withdrawal and treatment-emergent adverse events (TEAEs).. Five trials met the inclusion criteria. Compared with placebo, 20, 50, 100 and 150 mg/day BRV was associated with significantly higher 50% responder rates. In addition, the effect of 50 mg BRV on seizure freedom was significantly different than that of placebo. Both fatigue and nasopharyngitis were significantly associated with 20 mg BRV, whereas fatigue and irritability were associated with 50 mg BRV. Somnolence was associated with 150 mg BRV. No significant differences were observed for the other common TEAEs.. The use of BRV at doses > 5 mg/day resulted in statistically significant reduction in seizure frequency in respect to the 50% responder rate. BRV was reasonably tolerated by patients. These findings warrant confirmation in future studies.

Topics: Anticonvulsants; Combined Modality Therapy; Epilepsies, Partial; Fatigue; Humans; Irritable Mood; Placebo Effect; Pyrrolidinones; Seizures; Treatment Outcome

This long-term follow-up (LTFU) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses (maximum of 200 mg/day) in patients with focal seizures. The secondary objective was to evaluate the efficacy of BRV over time.. Two Phase III, randomized, double-blind, historical-controlled conversion-to-monotherapy trials (N01276: NCT00698581; N01306: NCT00699283) were conducted in patients aged ≥16 years with uncontrolled focal seizures. Patients who completed either of these core trials or who met a protocol-defined exit criterion could enter this LTFU trial (N01315; NCT00761774). Patients entered LTFU at a recommended BRV dose of 100 mg/day, with flexible dosing of 50-200 mg/day, as monotherapy or adjunctive therapy; additional AEDs could be prescribed and adapted in dose if clinically indicated. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables included duration of continuous monotherapy, reduction in focal seizure frequency and seizure freedom. Safety and efficacy variables were assessed for all patients in the safety set or efficacy set, respectively, regardless of BRV treatment regimen. In addition, a post hoc subgroup analysis was conducted for patients who completed the BRV monotherapy period in either core trial, and entered the LTFU on BRV monotherapy. For this subgroup, TEAEs were summarized by 3-month time intervals over the first 12 months of LTFU.. 108 patients were enrolled in the LTFU trial between November 2008 and February 2010. 79 (73.1 %) patients discontinued the LTFU trial, most commonly due to lack of efficacy [37 (34.3 %)] and adverse events [16 (14.8 %)]. At core trial baseline, patients had a median of 6.3 focal seizures/28 days and 53 (49.1 %) had failed ≥5 previous lifetime AEDs. During LTFU, 70 (64.8 %) patients had ≥12 months and 56 (51.9 %) patients had ≥24 months of BRV treatment. TEAEs were reported by 98 (90.7 %) patients; most commonly (≥15 % of patients) convulsion (17.6 %), nasopharyngitis (17.6 %), depression (16.7 %) and fatigue (15.7 %). Median percent reduction from baseline in focal seizure frequency/28 days was 56.8 %. Among 86 patients who completed at least 6 months of treatment, 29 (33.7 %) patients were seizure-free for ≥6 months and 22 (25.6 %) were seizure-free for ≥12 months. 50/108 patients were included in the BRV monotherapy subgroup; 33/50 (66.0 %) patients reported a TEAE in the core trials, while 26/50 (52.0 %), 15/37 (40.5 %), 14/33 (42.4 %) and 9/27 (33.3 %) patients reported any TEAE during LTFU months 1-3, 4-6, 7-9 and 10-12, respectively. In the BRV monotherapy subgroup, the most common TEAEs (≥5% of patients) during LTFU months 1-3 were fatigue [3/50 (6.0 %)] and dizziness [3/50 (6.0 %)].. Results from the LTFU trial support the long-term safety of BRV at individualized doses of up to 200 mg/day as a well-tolerated, and effective treatment for patients with focal seizures. Efficacy analyses indicate that seizure reductions with brivaracetam were generally maintained over time.

Topics: Adult; Anticonvulsants; Dizziness; Double-Blind Method; Fatigue; Female; Follow-Up Studies; Humans; Internationality; Male; Middle Aged; Pyrrolidinones; Seizures; Treatment Outcome

The objective was to assess the efficacy and safety of adjunctive brivaracetam (BRV) with concomitant use of lamotrigine (LTG) or topiramate (TPM) in patients with uncontrolled focal seizures.. Data were pooled from three randomized, placebo-controlled Phase III studies (NCT00490035/N01252, NCT00464269/N01253, NCT01261325/N01358) of adults with focal (partial-onset) seizures. Patients taking concomitant levetiracetam were excluded from the efficacy populations, but included in the safety populations. This post-hoc analysis reports data from patients taking BRV in the approved therapeutic range (50-200mg/day) concomitantly with LTG or TPM.. The number of patients in each of the three BRV dosage groups was small, particularly for the TPM subgroup. Mean percent reduction over placebo in baseline-adjusted focal seizure frequency/28days for BRV 50, 100, and 200mg/day was 8.7, 5.3, and 8.9 in the LTG subgroup (n=220), and 8.4, 21.3, and -4.2 in the TPM subgroup (n=122). The ≥50% responder rate with concomitant LTG or TPM with BRV 50, 100, and 200mg/day or placebo was LTG: 28.1%, 36.1%, 34.1%, and 29.1%; and TPM: 14.3%, 44.4%, 25.0%, and 17.5%. There were numerically ≥50%, ≥75%, ≥90%, and 100% responder rates for patients taking BRV ≥50mg/day compared with placebo in both subgroups. In the LTG and TPM safety populations (n=245 versus n=125), treatment-emergent adverse events (TEAEs) were reported with LTG 68.7% versus 68.4%, and TPM 65.6% versus 57.8% (BRV ≥50mg/day versus placebo). Discontinuations due to TEAEs versus placebo were LTG 7.3% versus 6.3% and TPM 8.2% versus 4.7%. The three most frequently reported TEAEs for both subgroups were somnolence, dizziness, and fatigue. Of these, the incidence of fatigue in the LTG population appeared to increase with dose.. In this post-hoc pooled analysis, BRV administered with concomitant LTG or TPM reduced seizure frequency and was generally well tolerated for BRV doses of 50-200mg/day.

Topics: Adult; Anticonvulsants; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Fatigue; Female; Humans; Lamotrigine; Male; Middle Aged; Pyrrolidinones; Seizures; Sleepiness; Topiramate; Treatment Outcome; Young Adult

Brivaracetam (BRV) is an anti-seizure drug for the treatment of focal and generalized epileptic seizures shown to augment short-term synaptic fatigue by slowing down synaptic vesicle recycling rates in control animals. In this study, we sought to investigate whether altered short-term synaptic activities could be a pathological hallmark during the interictal periods of epileptic seizures in two well-established rodent models, as well as to reveal BRV's therapeutic roles in altered short-term synaptic activities and low-frequency band spontaneous brain hyperactivity in these models. In our study, the electrophysiological field excitatory post-synaptic potential (fEPSP) recordings were performed in rat hippocampal brain slices from the CA1 region by stimulation of the Schaffer collateral/commissural pathway with or without BRV (30 μM for 3 h) in control or epileptic seizure (induced by pilocarpine (PILO) or high potassium (h-K

Topics: Animals; Anticonvulsants; Brain; Fatigue; Pilocarpine; Pyrrolidinones; Rats; Rodentia; Seizures; Synaptic Vesicles

Patients with intellectual disability (ID) are often excluded from clinical trials, and little is known about the best approach to treat their epilepsy. Brivaracetam (BRV) is a new antiepileptic drug (AED) for adjunctive treatment in patients with focal-onset seizures with or without secondary generalization. We analyzed the efficacy and tolerability of BRV in patients with ID and epilepsy who either had or had not previously received treatment with levetiracetam (LEV). Data on efficacy and tolerability were retrospectively collected. After the initial start of BRV in our tertiary epilepsy center, we analyzed medical records at 0, 3, 6 and 12 months of follow-up. 116 patients were included (mean age = 34.9 years, 44% female). All had complete data of 3-month follow-up, 76 of 6-month follow-up, and 39 patients of 1-year follow-up. Median starting dose of BRV was 50.0 mg/day and the mean number of concomitant AEDs was 2.6. Seizure reduction and no side effects were reported in more than half of all patients. The most reported side effects were somnolence, dizziness and aggression. Retention rates for BRV were 84.4%, 75.5% and 58.1% after 3, 6 and 12 months, respectively. Seizure reduction and side effects did not differ significantly between the groups with or without previous LEV treatment. We demonstrate that BRV is effective and well tolerated in patients with epilepsy and ID, even in those where previous LEV treatment failed.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Dizziness; Epilepsy; Fatigue; Female; Headache; Humans; Intellectual Disability; Male; Middle Aged; Pyrrolidinones; Retrospective Studies; Sleepiness; Treatment Outcome; Young Adult

This multicenter service evaluation explores the efficacy and tolerability of brivaracetam (BRV) in an unselected, consecutive population in 'real-life' clinical settings.. We retrospectively collected data from patient records at 11 UK hospitals and epilepsy centers. Consecutive patients prescribed BRV with at least 3 months of follow-up (FU) were included. Apart from reporting effectiveness and tolerability of BRV across the whole cohort, we compared treatment outcomes depending on previous levetiracetam use (LEV+ versus LEV-), comorbid learning disability (LD+ versus LD-), and epilepsy syndrome (focal versus generalized epilepsy).. Two hundred and ninety patients (46% male, median age: 38 years, range: 15 to 77) with ≥3 months of FU were included. The median duration of BRV exposure was 12 months (range: 1 day to 72 months). Overall BRV retention was 71.1%. While 56.1% of patients improved in terms of seizure frequency category (daily, weekly, monthly, yearly seizures), 23.1% did not improve on this measure and 20.8% deteriorated. In terms of seizure frequency, 21% of patients experienced a ≥50% reduction, with 7.0% of all patients becoming seizure-free. Treatment-emergent adverse events (AEs) were reported by 107 (36.9%) patients, but there were no serious AEs. The commonest AEs were sedation/fatigue (18.3%), mood changes (9.0%), and irritability/aggression (4.8%). There were no significant differences in drug retention, seizure frequency outcomes, or AEs between the LEV+ and LEV- subgroups, or between patients with generalized or focal epilepsies. Although 15.5% of patients in the LD+ group achieved a ≥50% reduction, this rate was lower than in the LD- group.. This 'real-life' evaluation suggests that reductions in seizure frequency can be achieved with BRV in patients with highly refractory epilepsy. Brivaracetam may be a useful treatment option in patients who have previously failed to respond to or tolerate LEV, those with LD, or (off-label) those with generalized epilepsies.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Cohort Studies; Epilepsies, Partial; Epilepsy, Generalized; Fatigue; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyrrolidinones; Retrospective Studies; Seizures; Treatment Outcome; United Kingdom; Young Adult