Brand Name to Generic Substitution of Levetiracetam in Patients with Epilepsy

PURPOSE: Levetiracetam is one of the most widely used antiepileptic drugs, but the evidence related to the safety of substitution from brand name to generic levetiracetam is scarce. The present study evaluated the risk of increased frequency of seizures after replacement of a brand-name levetiracetam with a generic product.

METHODS: We enrolled patients with epilepsy who were treated with branded levetiracetam for at least 6 months of sustained use. Patients were advised to switch to the generic levetiracetam. We analyzed data from 6 months before, to 6 months after, generic substitution. Increased seizure frequency was defined as a? 50% increase in seizure frequency after conversion date compared with seizure frequency before the conversion date. We analyzed changes in seizure frequency and performed subgroup analysis according to changes in seizure frequency.

RESULTS: We analyzed 148 epilepsy patients. Among the 148 patients, 109 (73.6%) were seizure-free before substitution and 105 patients remained seizure-free after switching. After generic substitution, an increased seizure frequency was noted in seven patients (4.7%), and a decreased seizure frequency was noted in 10 (6.8%). Patients with decreased seizure frequency were significantly younger (p?=?0.035) than those with an unchanged seizure frequency.

CONCLUSION: This study suggests that the risk of increased seizure frequency after generic substitution was minimal. The generic substitution of levetiracetam was generally safe, although larger prospective studies are warranted to corroborate our findings.

Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Sunovion Pharmaceuticals Inc. announced that Health Canada has approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy. All patients who participated in the monotherapy trial were newly or recently diagnosed with epilepsy.

APTIOM is now indicated in Canada as monotherapy and as adjunctive therapy for the treatment of partial-onset seizures (POS) in adults with epilepsy.

Partial-onset seizures are the most common type of seizures experienced by people living with epilepsy and, given these seizure’s unpredictable nature, can have a significant impact on their lives, said Eduard Bercovici, M.D., Epileptologist, director of the Southern Ontario Epilepsy Clinic. This new indication for APTIOM in Canada helps provide an additional treatment option for health care professionals and patients with partial-onset seizures.

The SNDS approval is supported by data from a Phase 3, double-blind, active controlled, non-inferiority study in which APTIOM met its primary efficacy endpoint of non-inferiority to the active comparator, carbamazepine controlled release (CBZ-CR).

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome

The LGS Foundation is pleased to announce that the US Food and Drug Administration (FDA) has approved EPIDIOLEX® (cannabidiol / CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients two years age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of anti-epileptic drugs.

“Today’s announcement gives individuals with Lennox-Gastaut Syndrome and their families much-needed hope,” says LGS Foundation Executive Director Christina SanInocencio. “Lennox-Gastaut syndrome is a devastating form of epilepsy and despite currently available FDA-approved medications and a poly-therapy approach to treatment, the majority of individuals with LGS will continue to have life-long, debilitating seizures, along with cognitive impairment and abnormal waves on the EEG (electroencephalogram).”

Cannabidiol (CBD) is a compound derived from the cannabis plant that does not produce a “high” and has been an increasing focus of medical research in epilepsy. Recently, study results from the clinical trial of EPIDIOLEX® published in the New England Journal of Medicine showed to significantly reduce the number of seizures in patients with Lennox-Gastaut Syndrome.

Along with the FDA’s approval for EPIDIOLEX® for seizures associated with Lennox-Gastaut syndrome, the approval is also indicated for another form of rare epilepsy that begins in childhood called Dravet syndrome.

Use of Brivaracetam in Genetic Generalized Epilepsies and for Acute, Intravenous Treatment of Absence Status Epilepticus

SIGNIFICANCE: Use of brivaracetam in genetic generalized epilepsies is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam to brivaracetam at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under levetiracetam, and a switch to brivaracetam can be considered in patients with levetiracetam-induced adverse events.

OBJECTIVE: The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice.

METHODS: A multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017.

RESULTS: A total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline.

The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months.

Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus.

Vigabatrin and High-Dose Prednisolone Therapy for Patients with West Syndrome

CONCLUSION: Using a treatment protocol involving vigabatrin and prednisolone for West syndrome (WS), 72.7% of patients showed resolution of spasms and a BASED score of ?2. This study also found that this drug administration protocol was safe. However, further studies are warranted as this study describes results from observational study with limited sample size.

OBJECTIVE: Hormonal therapy and vigabatrin are now accepted as the first-line or standard therapies for WS. However, the superiority of these drugs in terms of monotherapy or combination therapy is still in question. In this study, we designed a treatment protocol for WS and prospectively assessed the efficacy of these therapies in controlling spasms, stabilizing electroencephalography (EEG), and allowing for developmental catch-up.

METHODS: In patients diagnosed with WS, vigabatrin was first administered alone for 2 weeks, and then prednisolone was administered in combination with vigabatrin if patients did not respond to vigabatrin. The detailed drug administration protocol was as follows: vigabatrin 50?mg/kg/day for 1 day, followed by vigabatrin 100?mg/kg/day for 3 days, vigabatrin 150?mg/kg/day if spasms were still present or the burden of amplitudes and epileptiform discharges (BASED) score on EEG was ?3 on day 5; 40?mg/day of prednisolone was added if spasms were still present or the BASED score was ?3 on day 14. The prednisolone dose was increased to 60?mg/day if spasms were still present or the BASED score was ?3 on day 21.

RESULTS: Sixty-six patients newly diagnosed with WS (median seizure onset age: 5.7 [IQR, 4.1-7.1] months, median age at diagnosis: 6.6 [IQR, 5.4-8.1] months, n?=?40 [60.6%] boys) were subjected to the vigabatrin and prednisolone therapy protocol. Of the 66 patients, 22 (33.3%) patients showed resolution of spasms and a BASED score of ?2 after vigabatrin alone, and 26 (39.4%) patients showed resolution of spasms and a BASED score of ?2 after a combination of vigabatrin and prednisolone, for a total of 48 (72.7%) patients who were responsive to the protocol without relapse for at least 7 months after WS diagnosis. The mental and psychomotor age quotients were higher at the time of diagnosis and remained significantly higher 6 months after the diagnosis in responsive patients (p?<? 0.001). No serious adverse reactions leading to discontinuation or reduction of drug doses were observed.

The adult motor phenotype of Dravet syndrome is Associated with Mutation of the STXBP1 Gene and Responds Well to Cannabidiol Treatment

Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult; that is why Cannabidiol emerged as valid option for treatment of this condition.

Effects of Valproate on Reproductive Endocrine Function in Male Patients with Epilepsy: A Systematic Review and Meta-Analysis

CONCLUSIONS: This meta-analysis indicates that VPA may lead to a significant decrease in the levels of FSH and testosterone and alter the concentrations of LH, DHEAS, SHBG, and ADION to some extent, which might contribute to the reproductive endocrine dysfunction in male patients with epilepsy. It is important for clinical neurologists to be cautious when prescribing VPA to reproductive-aged male patients with epilepsy.

BACKGROUND: Valproate (VPA) is a broad spectrum antiepileptic drug (AED) that is generally used as a first line agent for most idiopathic and symptomatic generalized epilepsies. Many studies have indicated that AEDs cause reproductive endocrine disorders in males, but the exact etiology underpinning these dysfunctions is not clear. This meta-analysis and systematic review was intended to evaluate the effect of VPA on reproductive endocrine function in male patients with epilepsy.

METHODS: A literature search was performed using electronic databases up to December 2017 for eligible studies. The differences in the levels of the reproductive factors, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG), testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione (ADION) in the male patients with epilepsy treated with VPA (treatment group) were compared with the those of the healthy controls (control group) by the use of the Standardized mean difference (SMD) with 95% confidence intervals (CIs).

RESULTS: Six publications with a total of 316 subjects were identified. The result revealed that the levels of FSH (SMD?=?-1.33, 95% CI: -2.60 to -0.07, P?=?0.039) and testosterone (SMD?=?-0.45, 95% CI: -0.87 to -0.03, P?=?0.038) of the treatment group were decreased significantly compared with the healthy controls. There was an increase in the levels of SHBG (SMD?=?0.41, 95% CI: -0.21 to 1.03, P?=?0.197), DHEAS (SMD?=?0.20, 95% CI: -0.06 to 0.45, P?=?0.126) and ADION (SMD?=?0.73, 95% CI: -0.10 to 1.57, P?=?0.086), and a decrease in that of LH(SMD?=?-0.71, 95% CI: -1.49 to 0.07, P?=?0.075) in the male patients with epilepsy treated with VPA, but the differences did not reach statistical significance (P?>?0.05).

Clinical Trial to Investigate the Efficacy and Clinical Usability of Staccato Alprazolam (STAP-001) in Those with Epilepsy with a Predictable Seizure Pattern

The StATES trial (Inpatient, Dose-Ranging Study of Staccato Alprazolam in Epilepsy With Predictable Seizure Pattern) is a study to investigate the efficacy, safety and clinical usability of Staccato Alprazolam (STAP-001) in adult subjects (18 years and older) with epilepsy with a predictable seizure pattern.

Adult subjects that have an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes are eligible for this trial.

This is a multi-center, double-blind, randomized, in-patient study. Subjects will be admitted to a Clinical Research Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-patient unit will be 2-8 days.

What are the possible outcomes of this study?

Once the subject enters the CRU or EMU and has a seizure, they will be treated with STAP-001. One seizure per subject will be treated. STAP-001 is delivered orally to the deep lung for systemic delivery. The Staccato delivery system is user-friendly and easy to use and accomplished with a single, normal breath by the subject.

The duration and timing of the seizure event and occurrence of subsequent seizures will be assessed by the Staff Caregiver(s) through clinical observation and confirmed with video electroencephalogram (EEG).

The following measures will be assessed:

  • If the seizure stopped within two minutes of administering STAP-001
  • If seizures recurred within 2 to 12 hours after giving STAP-001
  • Seizure duration
  • Seizure severity
  • The use of rescue medication to stop a seizure that doesn’t respond to the study drug 5 minutes post-drug and for up to 2 hours post-drug

 

Who is eligible to participate in this study?

Subjects may be eligible to participate in this study if they meet certain inclusion criteria, including:

  • Subject is able to provide, personally signed and dated informed consent to participate in the study or will have a legally authorized representative (LAR) sign the informed consent on his or her behalf before completing any study related procedures
  • Male or female adult (18 years or older)
  • Subject has an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes that includes at least one of the following:
    • Generalized seizure episodes starting with a flurry of absence seizures or myoclonic seizures with a minimum duration of 5 minutes
    • Episodes of a prolonged focal seizure with a minimum duration of 3 minutes
    • Multiple (?2) focal seizures within a 2-hour time period
    • Prior to randomization, has experienced ?4 seizure episodes with predictable pattern during the last 4 weeks (qualification period) and no more than one week without a predictable seizure episode before the Screening Visit
  • Female participants (if of child-bearing potential and sexually active) and male participants (if sexually active with a partner of child-bearing potential) who agree to use a medically acceptable and effective birth control method throughout the study and for 1 week following the end of the study. Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide,intrauterine device (IUD), surgical sterilization, and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone
  • Subject is able to comply by the requirements of the protocol, particularly the requirements and specific Institution policies during the in-clinic stay

 

Who is not eligible to participate in the study: 

Potential participants will be excluded from the study if they meet the following exclusion criteria:

  • History or diagnosis of non-epileptic seizures (e.g. metabolic or pseudo-seizures)
  • History of status epilepticus in the 6 months prior to Screening
  • Has a progressive neurological disorder such as brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that is likely to progress in the next 3 months
  • Receiving chronic benzodiazepine treatment (defined as an average of ? 4 administrations per week) prior to admission to the in-patient unit
  • Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., ritonavir)
  • Has severe chronic cardio-respiratory disease
  • History of HIV-positivity
  • Pregnant or breast-feeding
  • Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the upper limit of normal (ULN) or creatinine ? 1.5 x ULN)
  • History of acute narrow angle glaucoma, Parkinson’s disease, hydrocephalus, or history of significant head trauma
  • Subjects who use medications to treat airways disease, such as asthma or COPD or have any acute respiratory signs/symptoms (e.g., wheezing)
  • Use of any investigational drug within 30 days or 5 half-lives of the investigational drug prior to administration of study medication, whichever is longer
  • A history within the past 1 year of drug or alcohol dependence or abuse
  •  Positive urine screen for drugs of abuse at Screening (positive Cannabis/Cannabinol results are acceptable if there is a documented history of stable use for medical purposes)

 

Are there any risks to participating in this study? 

In a prior study of the effects of STAP-001 in individuals with epilepsy, dose-related sedation was the most common adverse event. Overall, STAP-001 was well-tolerated and no serious adverse events were reported. Vital signs, heart rhythm, and brain activity will be monitored throughout the inpatient period of the study to monitor for sedation.

What is required of me? 

StATES is an in-patient study. The subjects will be admitted to a Clinical Research Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-patient unit will be 2-8 days. The total StATES trial will be about 8 to 12 weeks long, including the screening and follow-up periods.

After an initial screening in an outpatient visit, you will be followed for 4 weeks to make sure you are eligible for the study. During this period, you will record your seizure activity in a daily seizure diary. If your seizure pattern qualifies, you will be randomly assigned to either the study drug or a placebo. Neither you nor the study administrator will know which medicine you are getting.

The treatment phase of the study will occur next. You will be admitted to a CRU or EMU in anticipation of a seizure. After you have a seizure, you will be given one dose of STAP-001 or placebo. You will be followed for at least 12 hours after the medicine is given.

Following discharge from the CRU or EMU, your last study visit will be done by a phone call with a study coordinator 12-16 days after you received the study drug (STAP-001).

What is the total time involved?

The StATES study will take a total of 8 to 12 weeks.

What are the study time frames?

Actual study start date: March 16, 2018
Estimated Primary Completion Date: May 2019
Estimated Study Completion Date: May 2019

How do I find out more information about this study?

If you would like to see if you are eligible to participate please visit www.epilepsyhealthstudy.com. You may also contact the program director at: studydirector@engagetherapeutics.com.

New Technique Fine-Tunes Treatment for Severe Epilepsy Cases

One of three epilepsy patients experience no relief from drugs and are candidates for surgery. An advance by researchers at Yale and the Cleveland Clinic will enable surgeons to more precisely target areas of the brain causing debilitating symptoms in a subset of these patients.

The technology called magnetoencephalography or MEG measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and the researchers have developed a novel way to employ it.

Recording of seizures during routine MEG in some surgical candidates can help precisely identify affected areas of the brain and, in a few cases, even negate the need to conduct invasive intracranial EEG evaluations prior to surgery, the authors say. Lead author of the study published June 11 in the journal JAMA Neurology is Dr. Rafeed Alkawadri, assistant professor of neurology at Yale and director of Yale Human Brain Mapping Program. Dr. Andreas Alexopoulos of the Cleveland Clinic is senior author of the paper.

Transcutaneous Vagal Nerve Stimulation (t-VNS): An Adjunctive Treatment Option for Refractory Epilepsy

PURPOSE: The aim of this trial was to investigate the efficacy and safety of transcutaneous vagal nerve stimulation (t-VNS) in the palliative treatment of drug resistant epileptic patients ineligible for surgery.

METHODS: Twenty adult patients received four hours of t-VNS per day for six months (T1), followed by a two-month washout period (T2). The frequency and type of seizures recorded at T1 and T2 were compared with those occurring in the three months preceding study entry (T0). Responders (>30% reduction in the total number of seizures) subsequently received two hours of t-VNS per day for further six months (T3). All patients underwent electroencephalography (EEG) and completed the Quality of Life in Epilepsy questionnaire at baseline and T1.

RESULTS: At T1 six patients were considered responders. In these patients, at T3 the average reduction in seizure frequency was 60% compared to T0 (p?=?0.043), and 51% compared to T2 (p?=?0.043). Responders had more often seizures with falls (5 of 6; 83.3%) compared with non-responders (3 of 14; 21.4%) (p?=?0,010) and t-VNS reduced their frequency by a percentage ranging from 47.5 to 100%. There was no change in responders’ EEG findings after stimulation. At the end of the trial, three responders continued t-VNS, one implanted VNS.

CONCLUSIONS: t-VNS had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients. Further studies should be planned to assess whether t-VNS is a suitable tool to predict the efficacy of implanted VNS.