XEN1101 for Seizures (X-ACKT Trial)
Palo Alto (17 mi)Age: Any Age
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Xenon Pharmaceuticals Inc.
Stay on your current meds
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests XEN1101, a medication added to current treatments, in people with generalized epilepsy experiencing PGTCS who are already on 1-3 anti-seizure medications. The goal is to see if taking XEN1101 with an evening meal can help reduce seizure frequency.
Do I have to stop taking my current medications for the trial?No, you don't have to stop taking your current medications. In fact, you must stay on a stable dose of 1 to 3 allowable current anti-seizure medications (ASMs) for at least 1 month before the trial and throughout the study.
Is XEN1101 a promising drug for seizures?The information provided does not mention XEN1101, so we cannot determine if it is a promising drug for seizures based on the given research articles.13121315
What safety data is available for XEN1101 (and its other names) for seizures?The provided research does not contain safety data for XEN1101 or its other names (Azetukalner, Encukalner, VRX 621698, XEN-1101, XPF-008, 1OP 2198). The studies focus on oxcarbazepine and a novel compound PH192, neither of which are related to XEN1101.5891114
What data supports the idea that XEN1101 for Seizures is an effective drug?The available research does not provide any data on the effectiveness of XEN1101 for Seizures. The studies focus on xeroderma pigmentosum, a genetic disorder, and do not mention XEN1101 or its use for treating seizures.246710
Eligibility Criteria
This trial is for adults over 18 with a BMI ≤40 who have generalized epilepsy with tonic-clonic seizures despite trying at least two anti-seizure medications. They must be on a stable dose of their current meds and able to track their seizures. Excluded are those with recent severe seizure episodes, non-epileptic psychogenic seizures, or significant mental health issues.Treatment Details
The study tests XEN1101 as an additional treatment for epilepsy against a placebo in a double-blind setup, meaning neither the participants nor the researchers know who's getting the real drug versus the placebo during the trial.
3Treatment groups
Experimental Treatment
Placebo Group
Group I: XEN1101 25 mg/dayExperimental Treatment1 Intervention
XEN1101 25 mg/day
Group II: XEN1101 15 mg/dayExperimental Treatment1 Intervention
XEN1101 15 mg/day
Group III: PlaceboPlacebo Group1 Intervention
Placebo
Find a clinic near you
Research locations nearbySelect from list below to view details:
University of Maryland Medical CenterBaltimore, MD
Spectrum HealthGrand Rapids, MI
Mid-Atlantic Epilepsy and Sleep CenterBethesda, MD
UMass Memorial Medical CenterWorcester, MA
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Who is running the clinical trial?
Xenon Pharmaceuticals Inc.Lead Sponsor
Worldwide Clinical TrialsCollaborator
References
Gene mapping of SEZ group genes and determination of pentylenetetrazol susceptible quantitative trait loci in the mouse chromosome. [2019]Gene mapping of the newly discovered SEZ genes (seizure-related genes) in the mouse was performed by linkage analysis. SEZ6 was on chromosome 11, SEZ12 on chromosome 16, SEZ15 on chromosome 3 and SEZ17 (PTZ17) on chromosome 18. The mouse chromosomal locus related to high susceptibility to pentylenetetrazol (PTZ) was also determined by linkage analysis using the recombinant inbred mouse, BXD (C57BLxDBA). A significant level of PTZ susceptibility was found on chromosome 2. Chromosomal loci of the newly discovered SEZ genes were not coincident with the significant chromosomal loci to PTZ susceptibility. Since epilepsy is assumed to be a disease syndrome which is probably manifested by abnormal expression of multifocal genes, determination of the role of each chromosomal locus in the provocation of seizure activity is important.
Contribution of XPF functional domains to the 5' and 3' incisions produced at the site of a psoralen interstrand cross-link. [2019]XPF forms a heterodimeric complex with ERCC1 and is required for the repair of DNA interstrand cross-links. In association with ERCC1, it is involved in production of the 5' incision at the site of a psoralen interstrand cross-link as well as the 3' incision. The present study was carried out to determine the functional domains of XPF that are important in the production of the 5' and 3' incisions that occur at a site of a psoralen interstrand cross-link. Monoclonal antibodies (mAbs) were utilized that had been generated against polypeptide fragments of XPF and affinity-mapped to specific regions of XPF. These mAbs were examined for their ability to differentially inhibit production of dual incisions in DNA by normal human chromatin-associated protein extracts that contain XPF and ERCC1. These studies show that two regions of XPF, one N-terminal region from amino acids 12-166 and one C-terminal region from amino acids 702-854, are the most important in the production of the 5' incision. The same N-terminal region and the C-terminal region from amino acids 702-916 are also involved in the 3' incision, though to a much lesser extent. Since this C-terminal region corresponds to the proposed site of interaction of ERCC1 with XPF, these results suggest that binding of ERCC1 to XPF is critical for its ability to produce the 5' and 3' incisions at the site of an interstrand cross-link, possibly through activation or regulation of the endonucleolytic activity of the N-terminal domain of XPF.
Antiepileptic activity of Panax ginseng against pentylenetetrazole induced kindling in rats. [2014]In the present study, Panax ginseng was evaluated for its antiepileptic activity against pentylenetetrazole (PTZ) induced chemical kindling in rats. PTZ was injected at the dose of 30 mg/kg, i.p. on alternate days and the occurrence of generalized tonic clonic convulsions were considered as the end point. One group received Panax ginseng every day, at a dose of 100 mg/kg, 30 min prior to PTZ injection whereas the other group received an equal volume of distilled water to serve as control. In a separate group the rats were evaluated for motor performance tests after Panax ginseng. The rats treated with Panax ginseng showed significant protection as compared to vehicle treated PTZ injected rats. The study suggests to potential of Panax ginseng against seizures.
Convulsive episodes in patients with group A xeroderma pigmentosum. [2006]To clarify the incidence of convulsive episodes in patients with group A xeroderma pigmentosum (XPA).
Open prospective study on oxcarbazepine in epilepsy in children: a preliminary report. [2018]To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in children with epilepsy.
Xeroderma pigmentosum: a glimpse into nucleotide excision repair, genetic instability, and cancer. [2019]Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by extreme sensitivity to sunlight and severe predisposition to UV-induced skin cancer. Seven genes, ranging from XPA to XPG, are defective in XP. These genes are important components of the nucleotide excision repair (NER) system, which removes DNA damage induced by solar radiation, thereby preventing genome instability and carcinogenesis. In addition, XPV patients are defective in a translesion synthesis activity specialized in bypassing UV-induced lesions, and share symptoms with other XP patients. This review will focus on the evidence that elucidates the link between defective NER, genetic instability, and oncogenesis.
c.1643_1644delTG XPC mutation is more frequent in Moroccan patients with xeroderma pigmentosum. [2022]Xeroderma pigmentosum is a rare autosomal recessive disease characterized by hypersensitivity to UV light which is due to alterations of the nucleotide excision repair pathway. Eight genes (XPA to XPG and XPV) are responsible for the disease. Among them, the XPC gene is known to be the most mutated in Mediterranean patients. The aim of this study was to determine the frequency of the most common XPC mutation and describe the clinical features of Moroccan patients with xeroderma pigmentosum. Twenty four patients belonging to 21 unrelated Moroccan families and 58 healthy subjects were investigated. After clinical examination, the screening for the c.1643_1644delTG (p.Val548AlafsX25) mutation in the XPC gene was performed by PCR and automated sequencing of exon 9 in all patients and controls. The molecular analysis showed that among the 24 patients, 17 were homozygous for the c.1643_1644delTG mutation and all their tested parents were heterozygous, whereas the others (7 patients) did not carry the mutation. The frequency of this mutation was estimated to be 76.19 % (16/21 families). None of the 58 healthy individuals carried this mutation. In addition, clinical investigation showed that the majority of the patients bearing this mutation have the same clinical features. Our results revealed that the p.Val548AlafsX25 mutation is the major cause (76.19 %) of xeroderma pigmentosum in Moroccan families. This would have an important impact on improving management of patients and their relatives.
[Clinical efficacy of oxcarbazepine suspension in children with focal epilepsy]. [2018]To investigate the clinical efficacy and safety of oxcarbazepine (OXC) suspension in children with focal epilepsy.
Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial. [2021]To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization.
Dexmedetomidine and ketamine combination for a patient with xeroderma pigmentosa. [2021]Patients of xeroderma pigmentosa (XP) have increased sensitivity to ultraviolet light and a defective nucleotide excision repair (NER) mechanism in their DNA. Several types of neurological, dermatological, and ophthalmological complications are common in these patients. There is increasing evidence of delayed recovery and worsening of neurological status following general anesthesia in such patients. Some reports have shown uneventful conduct of total intravenous anesthesia in patients of XP. The authors report a case of XP in a young girl for surgery, previously anesthetized with delayed recovery, managed successfully with a combination of intravenous dexmedetomidine and ketamine.
Long-term efficacy and safety of adjunctive extended-release oxcarbazepine (Oxtellar XR® ) in adults with partial-onset seizures. [2021]Label="OBJECTIVE" NlmCategory="OBJECTIVE">To evaluate long-term outcomes of adjunctive therapy with SPN-804 (Oxtellar XR® , Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), in adults with refractory partial-onset seizures.
Apigenin reverses behavioural impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus. [2020]Objectives: Apigenin is the most common bioflavonoid known to be biologically active after systemic administration and show multiple pharmacological effects. The present study was designed to explore the role of apigenin in pentylenetetrazole (PTZ) kindling associated cognitive and behavioural impairments in the mouse model. Methods: The animals were kindled by injecting a sub-convulsive dose of PTZ (35 mg/kg) on every alternate day, followed by 20 days treatment with apigenin at two different doses (10 and 20 mg/kg). Seizure severity was assessed on every 5th, 10th, 15th, and 20th day during apigenin treatment after a PTZ injection, followed by analysis of cognitive and behavioural functions. Results: Apigenin treatment displayed insignificant effect on seizure severity in kindled mice at both the tested doses, in comparison to control. However, the treatment showed marked increase in per cent spontaneous alterations and decline in the anxiety index in T-maze and elevated plus maze tests, respectively. Apigenin-treated groups showed significant decrease in immobility period in both forced swim and tail suspension tests, without any change in the total locomotor activity in the open field test. Furthermore, increase in the hippocampus protein expression of brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and phosphorylated CREB, with increased serotonin level were also observed in the treated animals. Discussion: The results of the present study showed that apigenin treatment prevents cognitive deficit and reverses behaviour impairments, without altering seizures severity in kindled mice. The observed effects can be attributed to CREB-BDNF upregulation in the hippocampus.
[COMPARISON OF CHRONIC ANTICONVULSANT ACTIVITY AND SAFETY OF IEM-2062, SODIUM VALPROATE AND ME-MANTINE IN THE PENTYLENETETRAZOL KINDLING MODEL IN RATS]. [2018]IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], causing a combined block NMDA and AMPA receptors, after chronic oral administration in doses, respectively, 0.3 and 3 mg/kg, induce maximal anticonvulsant effect in the pentylenetetrazol kindling rats because decrease the number of completely kindling rats by 100 %, and also decrease in 2.5-3.3 times the average severity of clonic-tonic kindling seizures. IEM-2062 causes significant anticon- 299 vulsant effects in the widest range of doses, 1-48 mg/kg, which is 24-22 times more than that of memantine (12-20 mg/kg) and sodium valproate (100-200 mg/kg). Sodium valproate and memantine cause significant disturbances of locomotor activity in the «open field» test in doses causing maximal anticonvulsant effect in the kindling rats. At the same time IEM-2062 cause disturbance of locomotor activity only in very high dose of 92 mg/kg, which exceeds in 30.7 times the dose causing the maximum anticonvulsive effect in the kindling rats. Thus, IEM-2062 reduces the severity of kindling seizures in 1.7-1.9 times stronger than sodium valproate and memantine and also by 30.7 times is safer than sodium valproate and memantine.
A novel oxazolidinone derivative PH192 demonstrates anticonvulsant activity in vivo in rats and mice. [2019]The pharmacotherapeutic management of seizure disorders with currently available medications is not optimal due to side effects and failure of some patients to respond to all available medications. As such there is the need to develop new antiseizure drugs by looking at new chemical classes of compounds. We recently screened, in vitro, a new class of compounds, the oxazolidinones, for actions in the brain that may indicate potential for antiseizure activity. A few compounds were identified with such a potential. Here we tested whether one of these lead compounds, PH192, will exhibit in vivo antiseizure activity using chemically- and electrically- induced seizures models in mice and rats. Out of 5 compounds tested, all of them had minimal neurotoxicological effects in mice, with PH192 being the best, with comparable efficacy (ED50) and toxicity (TD50) to only levetiracetam. Intraperitoneal (IP) pretreatment with PH192 produced a dose-dependent protection of mice from seizures induced using the 6 Hz stimulation protocol with an estimated ED50 of 34.5 mg/kg in mice and about 90 mg/kg in rats and a neurotoxic dose >500 mg/kg in mice, yielding a calculated neuro (protective) index of >14.7. When pretreated with 100 mg/kg PH192 for 30 min, about 75% of mice were protected from 6 Hz-induced seizures. When rats were pretreated for 30 min with PH192, 66.6% of rats were protected from seizures induced using the 6 Hz stimulation protocol while 83.3% were protected using the maximal electroshock (MES) stimulation protocol. Pentylenetetrazole (PTZ) injection at 50, and 100 mg/kg produced stage 5 seizures in all rats. Thirty minutes IP pretreatment of rats with 100 mg/kg PH192 protected 80% of rats from the PTZ-induced seizures, a level of protection similar to that obtained with a reference antiepileptic drug (AED) phenytoin (40 mg/kg), that is used clinically for the treatment of various seizure disorders. The results of these studies indicate that PH192 protects against both chemically- and electrically-induced seizures with little central nervous system side effects. This suggests that the oxazolidinone pharmacophore has potential for discovering new antiepileptic drugs with possibly minimal central side effects.
Loss of presenilin 2 age-dependently alters susceptibility to acute seizures and kindling acquisition. [2021]Patients with Alzheimer's disease (AD) experience seizures at higher rates than the general population of that age, suggesting an underexplored role of hyperexcitability in AD. Genetic variants in presenilin (PSEN) 1 and 2 genes lead to autosomal dominant early-onset AD (ADAD); patients with PSEN gene variants also report seizures. Pharmacological control of seizures in AD may be disease-modifying. Preclinical efficacy of FDA-approved antiseizure drugs (ASDs) is well defined in young adult rodents; however, the efficacy of ASDs in aged rodents with chronic seizures is less clear. The mechanism by which ADAD genes lead to AD remains unclear, and even less studied is the pathogenesis of epilepsy in AD. PSEN variants generally all result in a biochemical loss of function (De Strooper, 2007). We herein determined whether well-established models of acute and chronic seizure could be used to explore the relationship between AD genes and seizures through investigating whether loss of normal PSEN2 function age-dependently influenced susceptibility to seizures and/or corneal kindling acquisition. PSEN2 knockout (KO) and age-matched wild-type (WT) mice were screened from 2- to 10-months-old to establish age-dependent focal seizure threshold. Additionally, PSEN2 KO and WT mice aged 2- and 8-months-old underwent corneal kindling such that mice were aged 3- and 9-months old at the beginning of ASD efficacy testing. We then defined the dose-dependent efficacy of mechanistically distinct ASDs on kindled seizures of young versus aged mice to better understand the applicability of corneal kindling to real-world use for geriatric patients. PSEN2 KO mice demonstrated early-life reductions in seizure threshold. However, kindling acquisition was delayed in 2-month-old PSEN2 KO versus WT mice. Young male WT mice took 24.3 ± 1.3 (S.E.M.) stimulations to achieve kindling criterion, whereas age-matched PSEN2 KO male mice took 41.2 ± 1.1 stimulations (p