Clinical Trail: Study to Investigate Safety and Tolerability of Intravenous Lacosamide in Children

The ASPIRE study is investigating whether Lacosamide (Vimpat®) given intravenously (into the vein) is safe for children and what it does in the body. This study enrolls children who are between 1 month and 16 years of age who have epilepsy, and for whom intravenous infusion is an option. All children will receive Lacosamide for a period that can last up to 45 days, but may be as short as one day, depending on the child’s condition. The study is running in a total of seven countries, including the US.

Eligibility Criteria:

Ages Eligible for Study: 4 Years to 16 years (child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Male or female from >=4 to <17 years of age
  • Subject has a diagnosis of epilepsy with partial-onset seizures or primary generalized tonic-clonic seizures
  • Subject meets 1 of the following criteria:
    • Open-label lacosmide (OLL) subject: Subject is currently receiving oral lacosmide (LCM) as adjunctive or monotherapy as participants in an open label long-term study (SP848, EP0034, or other pediatric study); OR,
    • Prescription lacosamide (RxL) subject: Subject is currently receiving prescribed oral LCM from commercial supply (eg, VIMPAT) as adjunctive or monotherapy; OR,
    • Initiating intravenous lacosamide (IIL) subject: Subject is not currently receiving LCM and will receive intravenous (iv) LCM as adjunctive treatment in EP0060. Initiation of LCM monotherapy is not permitted in IIL subjects.
  • Subject is an OLL or RxL subject and meets both of the following criteria:
    • Subject has been administered LCM for the treatment of epilepsy for at least 2 weeks prior to Screening; AND,
    • Subject has been administered (OLL) or prescribed (RxL) oral LCM at a dose of 2mg/kg/day to 12mg/kg/day (for subjects <50kg) or 100mg/day to 600mg/day (for subjects >=50kg). Open-label study drug LCM (OLL) or prescribed oral LCM dose (RxL) must be stable for at least 3 days prior to first LCM infusion; OR,
  • Subject is an ILL subject and is on a stable dosage regimen of at least 1 antiepileptic drug (AED). The daily dosage regimen of concomitant AED therapy must be kept constant for a period of at least 2 weeks prior to Screening.
  • Subject is an acceptable candidate for venipuncture and iv infusion
  • Subject is, in the opinion of the investigator, able to comply with all study requirements. Subject (or parent[s] or legal representative) is willing to comply with all study requirements

 

Exclusion Criteria:

  • Subject has previously received intravenous (iv) lacosamide (LCM) in this study
  • Subject has any medical, neurological, or psychiatric condition that, in the opinion of the investigator, could jeopardize the subject’s health or compromise the subject’s ability to participate in EP0060
  • Subject has clinically significant hypotension or bradycardia in the opinion of the investigator
  • Subject >=6 years of age has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by positive responses (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening

Vagus Nerve Stimulation (VNS) Therapy Update

Vagus nerve stimulation (VNS) therapy has been an option to treat pharmacoresistant seizures for 30?years. In this update, researchers review the clinical data that support the device’s efficacy in children, adolescents, and adults. They also review its side-effect profile, quality of life and cost benefits, and the impact the device has on sudden unexpected death in epilepsy (SUDEP). Researchers then discuss candidate selection and provide guidance on dosing and future models.

Vagus nerve stimulation therapy is an effective treatment for many seizure types and epilepsy syndromes with a predictable and benign side-effect profile that supports its role as the most commonly prescribed device to treat pharmacoresistant epilepsy.

Zogenix Announces Positive Top-line Results from Second Pivotal Phase 3 Clinical Trial of ZX008 in Dravet Syndrome

Zogenix, Inc. reported positive top-line results from its second confirmatory Phase 3 study (Study 1504) for its investigational drug, ZX008 (low-dose fenfluramine hydrochloride), for the treatment of children and young adults with Dravet syndrome. The study results, which are consistent with those reported in Study 1, Zogenix’s first pivotal Phase 3 study, successfully met the primary endpoint and all key secondary endpoints, demonstrating that ZX008, at a dose of 0.5 mg/kg/day (maximum 20 mg/day), is superior to placebo when added to a stiripentol regimen.

Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

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

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

Learn More

New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

Learn More

Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

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

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

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Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

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Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

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Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

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Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

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Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

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Open-Label Use of Highly Purified CBD (Epidiolex®) in Patients with CDKL5 Deficiency Disorder and Aicardi, Dup15q, and Doose Syndromes

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.

METHODS: We included patients aged 1-30?years with severe childhood-onset epilepsy who received CBD for ?10?weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n?=?20), Aicardi syndrome (n?=?19), Dup15q syndrome (n?=?8), and Doose syndrome (n?=?8). These patients were treated at 11 institutions from January 2014 to December 2016.

RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n?=?46] to week 12 (51.4% [n?=?35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n?=?27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, ?2(2)?=?22.9, p?=?0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.

SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12?weeks to 48?weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Open-label use of Highly Purified CBD (Epidiolex®) in Patients with CDKL5 Deficiency Disorder and Aicardi, Dup15q, and Doose Syndromes

OBJECTIVE: Researchers studied their collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.

METHODS: The study included patients aged 1-30?years with severe childhood-onset epilepsy who received CBD for ?10?weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n?=?20), Aicardi syndrome (n?=?19), Dup15q syndrome (n?=?8), and Doose syndrome (n?=?8). These patients were treated at 11 institutions from January 2014 to December 2016.

RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n?=?46] to week 12 (51.4% [n?=?35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n?=?27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, ?2(2)?=?22.9, p?=?0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.

SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12?weeks to 48?weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Switching Brain Circuits On and Off Without Surgery

In the maze of our brains, there are various pathways by which neural signals travel. These pathways can go awry in patients with neurological and psychiatric diseases and disorders, such as epilepsy, Parkinson’s, and obsessive-compulsive disorder. Researchers have developed new therapeutic strategies to more precisely target neural pathways involved in these conditions, but they often require surgery.

The latest findings from the laboratory of Mikhail Shapiro, assistant professor of chemical engineering at Caltech, are now showing how scientists and doctors might, in the future, selectively turn neural circuits on and off–without the need for surgery. The new study, featured in the July 9 online edition of Nature Biomedical Engineering, demonstrates how the method–which involves a trio of therapies: ultrasound waves, gene therapy, and synthetic drugs–can be used to specifically alter memory formation in mice.

“By using sound waves and known genetic techniques, we can, for the first time, noninvasively control specific brain regions and cell types as well as the timing of when neurons are switched on or off,” says Shapiro, who is also a Schlinger Scholar and a Heritage Medical Research Institute Investigator. The work has implications for basic research in animals and for the future treatment of neurological and psychiatric conditions.

The researchers say they hope to continue testing in animals with models of diseases such as epilepsy. Many patients with epilepsy currently undergo surgery to cut out the regions of their brain where seizures are thought to be triggered. With the ATAC method, specific brain areas could, in theory, be switched off temporarily without surgery.

Clinical Trial: Does Brivaracetam Have Faster Onset Time & Greater Effect Than Levetiracetam in Epilepsy Pts Using PPR Pharmacodynamic Efficacy Endpoint

The main purpose of this study is to see whether brivaracetam has a faster onset time and greater effect than levetiracetam in subjects with photosensitive seizures. Part 1 of the study will compare the effects of levetiracetam 1500 mg with the effects of brivaracetam 100 mg. Part 2, will compare the effects of levetiracetam 1500 mg with the effects of brivaracetam 100 mg or will compare the effects of levetiracetam 500mg with the effects of brivaracetam 25 mg.

Estimated study start date: June 1, 2018
Estimated study completion date: February 2019

Eligibility Criteria

Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria

  • Patients between 18 and 65 years of age
  • Male or female
  • PPR at minimum at 60,50,40,30,25,20,18 or 16 Hz as upper threshold
  • Drug naïve or at most with up to 4 AEDs, not being LEV or BRV

 

Exclusion Criteria

  • Current treatment with more than 4 AEDs
  • LEV or BRV as current treatment or used in the previous month.
  • History of severe side-effects or psychological side-effects with LEV or BRV use
  • Being pregnant or insufficiently protected against pregnancy (see also ref 31) or lactating Female
  • Serious internal medical disease (renal/hepatic/cardiovascular disease) as deemed by the on-site physician (WER)
  • History of psychiatric disease that has been a reason for acute hospitalisation for their condition of depression, schizophrenia, mania, delirium or aggressive behaviour
  • History of status epilepticus
  • History of significant ethanol or illicit drug use

Research Sheds Light on Composition of Cannabis Used to Treat Children with Epilepsy

study has found Australian parents who turned to medicinal cannabis to treat children with epilepsy overwhelmingly (75%) considered the extracts as “effective”. Contrary to parental expectations, extracts generally contained low doses of cannabidiol (CBD) – commonly considered to be a key therapeutic element and that has been successfully used in recent clinical trials to treat epilepsy.

The research, which commenced two years ago by the University of Sydney’s Lambert Initiative for Cannabinoid Therapeutics, not only sheds light on the composition of cannabis used in the community but also reveals the legal, bureaucratic, and cost issues faced by families who relied on the products, as well as demonstrating the barriers to accessing medicinal cannabis.

The study found that the main psychoactive ingredient in cannabis, tetrahydrocannabidiol (THC), and the closely related compound THCA, were present in most extracts, although the quantity was generally not enough to produce intoxicating effects. Just over half the extracts were associated with a seizure reduction of 75%-100%, which reinforces observations from animal studies and case reports of anticonvulsant effects of THC and THCA. As well, 65% were associated with other beneficial effects like improved cognition (35%) and language skills (24%).

Study Using i2b2 Could Help Standardize Use of Therapeutic Comas for Epileptic Patients

Status epilepticus (SE), a dangerous condition in which epileptic seizures follow one another for a duration of five or more minutes without the victim’s regaining consciousness between them, is the second most common neurological emergency in the United States, with a recorded maximum of around 150,000-plus cases per year. In 60-70 percent of cases, the patient responds to antiepileptic medications and benzodiazepines.

But a combination of those medications doesn’t always work, says Wolfgang Muhlhofer, M.D., an assistant professor of neurology in the University of Alabama at Birmingham Epilepsy Center. Up to 44 percent of status epilepticus cases progress to refractory status epilepticus (RSE), where the patient doesn’t respond to those drugs, and more extreme treatments have to be used.

“These emergencies require prompt and effective treatment,” Muhlhofer said. “The longer SE is going on, the higher the chances of brain damage or the body’s being unable to compensate for the trauma, leading to other complications like cardiac arrest or kidney or heart failure. There’s a lot of risk associated with this condition.”

Muhlhofer wanted to analyze RSE patients in a more systematic way, with the hopes of determining more specific guidelines regarding the lengths of what he calls “therapeutic coma.” He designed a study of adult patients, admitted to UAB or University of California, San Francisco Medical Center during a seven-year period, who were placed in an artificial coma and who had a seizure recurrence within the first 48 hours of lightening the patient’s sedative medications.

While artificial coma is the agreed-upon treatment for RSE patients, Muhlhofer says there isn’t an evidence-based consensus on how long patients should be kept in this state, and recent studies of this patient population have shown that, the longer a patient is kept in an artificial coma, the more likely they are to have complications during their hospitalizations or, worse, permanent problems with physical and cognitive functions.