Available essential tremor (ET) therapies have limitations.

Neuropathic pain affects ~ 6.9–10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage‐dependent and use‐dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo‐controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7‐day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax), area under the concentration‐time curve from predose to 24 hours postdose (AUC0–24), time to Cmax (Tmax), and terminal half‐life (t1/2), among others, were assessed. Drug‐related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug‐related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1–2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady‐state was achieved from day 5 onward. These data indicate that oral vixotrigine is well‐tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

Vixotrigine is a voltage- and use-dependent sodium channel blocker in development for neuropathic pain management. This study evaluated the effect of coadministration of vixotrigine (metabolized primarily via uridine diphosphate-glucuronosyltransferases) and an oral contraceptive containing ethinyl estradiol (uridine diphosphate-glucuronosyltransferase inducer) and levonorgestrel on the pharmacokinetics and safety of all three compounds. In this phase I, open-label, fixed-sequence, multiple-dose study, 36 healthy women received oral vixotrigine 150 mg three times daily for 6 days and once on day 7. This was followed by a washout period, days 8–11. The oral contraceptive was administered alone on days 12–25 and with vixotrigine 150 mg three times daily on days 26–32. Serial blood samples were collected for pharmacokinetic analysis. Safety was assessed. The geometric least-squares mean ratios (90% confidence intervals) for the area under the concentration-time curve over 8 h and maximum concentration of vixotrigine co-administered with an oral contraceptive vs vixotrigine alone were 0.85 (0.82–0.89) and 0.91 (0.87–0.96), respectively. The geometric least-squares mean ratios (90% confidence interval) for area under the concentration-time curve over 24 h and maximum concentration of ethinyl estradiol with vixotrigine vs ethinyl estradiol alone were 0.94 (0.91–0.97) and 0.89 (0.84–0.94), respectively; the ratios for levonorgestrel with vixotrigine vs levonorgestrel alone were 1.06 (0.98–1.16) and 1.05 (0.98–1.13), respectively. No adverse events occurring with vixotrigine alone were deemed related to the study drug by the investigators. Coadministration of vixotrigine and an oral contraceptive containing ethinyl estradiol and levonorgestrel had no clinically relevant effect on exposure of all three compounds. ClinicalTrials.gov registration number: NCT03324685 (registered 25 October, 2017).

Thursday, April 30April 14, 2020Free AccessEfficacy and Safety of CX-8998 in T-CALM, a Randomized, Double-Blind, Placebo-Controlled, Phase 2a Trial in Participants With Essential Tremor: Subgroup Analysis by Baseline Tremor Severity (1842)Hyder A. Jinnah, Spyros Papapetropoulos, Margaret Lee, Stacey Boyer, Evan Newbold, Rajesh Pahwa, Kelly E. Lyons, … Show All … , Rodger Elble, William Ondo, Theresa Zesiewicz, Peter Hedera, Adrian Handforth, Jenna Elder, and Mark Versavel Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1842 Letters to the Editor

Vixotrigine is a voltage‐ and use‐dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate‐glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first‐line treatment for trigeminal neuralgia. We conducted a double‐blind, randomized, placebo‐controlled, parallel‐group, single‐center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1‐3 and 200 mg twice a day, days 4‐21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole‐blood samples were collected for PK assessment. Statistical analyses were performed on the log‐transformed PK parameters area under the concentration‐time curve within a dosing interval (AUC0‐tau) and maximum observed concentration (Cmax) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0‐tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0‐tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0‐tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.

April 26, 2018April 10, 2018Free AccessA Phase 2a Study of CX-8998, an Oral, Potent and Selective T-Type Calcium Modulator in Adolescents and Young Adults with Absence Epilepsy: Rationale for population and dose selection (P5.282)Spiridon Papapetropoulos, Margaret Lee, Stacey Boyer, and Mark VersavelAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement) Letters to the Editor

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

INTRODUCTION:SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT.METHODS:Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry.RESULTS:Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings.CONCLUSION:CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

In Brief Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial. The ACTTION PROTECCT training system for 0 to 10 average pain intensity numerical rating scale led to modest benefits. Further research in a prospective treatment trial is needed.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T1 compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T1 compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

On April 30th, 2011 the National Institute of Neurological Disorders and Stroke (NINDS) held a workshop to identify key problems in recent epilepsy clinical trials and propose approaches to address the barriers that impede development of new therapeutic options for epilepsy. Preliminary recommendations were made for selection criteria for subjects entered into epilepsy trials that maximize the scientific impact of the trial and increase the ability to recruit appropriate subjects efficiently and safely. These recommendations were further refined by the authors following the workshop, and subsequently shared with all NINDS workshop participants and with the participants of the 2011 AED XI workshop on epilepsy trials (approximately 200 participants) for further comment. The working group agreed to a final set of criteria that include updated considerations of subject age, clinical semiology, EEG and imaging results, use of prior and current therapies, co-occurring conditions, and suicidality, among others.

Objective: Eslicarbazepine acetate (ESL) is a novel AED currently in development in the US as adjunct treatment for partial-onset seizures. Background Cognitive dysfunction is frequently observed in patients with epilepsy and represents an important challenge in the management of patients with this disorder. 1 In this respect, the contribution of antiepileptic drugs (AEDs) is of relevance, and studies in healthy volunteers have shown that AEDs produce cognitive effects. 1,2 Design/Methods: 797 subjects in the safety population were studied. Investigators recorded adverse events at each visit from Visit 1 and throughout the study (including at early discontinuation and at the post study visit). A Treatment Emergent Adverse Events (TEAE) was defined as an event that occurred on or after the date of first dose, or the date of randomization if the dates of the first dose or the onset of the event were missing or incomplete. All TEAEs affecting any aspect of cognition were tabulated. Results: TEAEs identified as related to cognition were disturbance in attention, memory impairment, amnesia, aphasia, bradyphrenia, and psychomotor retardation. The incidence of these TEAEs was ≤ 2% in all ESL dose groups. The highest incidence occurred in the ESL 1200 mg group, with bradyphrenia and aphasia only observed in this dose group. Conclusions: In this analysis, treatment with eslicarbazepine acetate as adjunct therapy to 1 to 3 concomitant AEDs was associated with a low incidence of cognitive TEAEs. References: 1. Mula M, et al. Antiepileptic drug-induced cognitive adverse effects. CNS Drugs . 2009;23:121-137. 2. Meador KJ. Cognitive and memory effects of the new antiepileptic drugs. Epilepsy Research . 2006;68:63-67. Supported by: BIAL - Portela & Ca, SA. Data analysis and editorial support provided by Sunovion Pharmaceuticals, Inc. Disclosure: Dr. Versavel has received personal compensation for activities with Sunovion Pharmaceuticals Inc. as an employee. Dr. Meador has received research support from Cyberonics, Neuropace, Pfizer, and UCB Pharma. Dr. Blum has received personal compensation for activities with Sunovion Pharmaceuticals Inc as an emplyee. Dr. Blum holds stock and/or stock options in GlaxoSmithKline, which sponosred research in which Dr. Blum was involved as an investigator. Ms. Zummo has received personal compensation for activities with Sunovion Pharmaceuticals Inc. Dr. Tripp has received personal compensation for activities with Sunovion Pharmaceuticals Inc. as an employee. Dr. Soares da Silva has received personal compensaiton for activities with Bial-Portela & Co., S.A. as an employee.

Objective: Evaluate predictors of hyponatremia (defined at different levels) in association with the use of eslicarbazepine acetate (ESL) 800 mg and 1200 mg as adjunct treatment to 1-3 concomitant anti-epileptic drugs (con-AEDs). Background Eslicarbazepine acetate is a novel sodium (Na + )-channel blocking antiepiletic drug (AED). Hyponatremia may develop during treatment with sodium channel AEDs. In two phase III clinical trials of ESL sodium levels + Design/Methods: Data from 790 subjects included in 2 Phase III trials were analyzed. For each subject the minimum post-dose Na + level was defined. Predicted values for log transformed minimum post-dose Na + levels were obtained from an ANCOVA model with treatment group, baseline Na + , con-AED, and the interaction of baseline Na + and con-AED as fixed effects. Probabilities of minimum post-dose Na + levels for ESL 800 mg and 1200 mg were calculated using the cumulative standard normal distribution: z=[log(x)-predicted value from model]/Sqrt MSE from model where x=125 mEq/L,130 mEq/L, 135 mEq/L. Results: Carbamazepine ([CBZ] n=467), lamotrigine ([LMT] n=186), valproic acid ([VPA] n=186) and levetiracetam ([LEV] n=96) were the most common con-AEDs. The combination of low baseline Na + and concomitant CBZ was associated with a higher probability of minimum post-treatment Na + + , the incidence of Na + Conclusions: The risk of developing hyponatremia (Na + + and those taking CBZ. Supported by: BIAL - Portela & Ca, SA. Data analysis and editorial support provided by Sunovion Pharmaceuticals Inc. Disclosure: Dr. Cheng has received personal compensation for activities with Sunovion Pharmaceuticals, Inc. Ms. Zummo has received personal compensation for activities with Sunovion Pharmaceuticals Inc. Dr. Sousa has received personal compensation for activities with BIAL as an employee. Dr. Versavel has received personal compensation for activities with Sunovion Pharmaceuticals Inc. as an employee. Dr. Blum has received personal compensation for activities with Sunovion Pharmaceuticals Inc as an emplyee. Dr. Blum holds stock and/or stock options in GlaxoSmithKline, which sponosred research in which Dr. Blum was involved as an investigator.

Objective: It is not known if the efficacy of adjunct eslicarbazepine acetate (ESL) varies based on concomitant antiepileptic drug (con-AED). Background Eslicarbazepine acetate (ESL) is a novel voltage-gated sodium channel blocker not approved for use in the United States. Two double-blind, placebo-controlled Phase III studies evaluated ESL once-daily (QD) as adjunct therapy in patients with partial-onset seizures. Design/Methods: We studied subjects (N=790) in the intent-to-treat population who received at least 1 dose of study medication (ESL 400 mg QD, 800 mg QD, 1200 mg QD or placebo) added to1-3 concomitant AEDs, and had at least 1 post-dose seizure assessment in the two studies. An exploratory analysis on the impact of con-AEDs on efficacy was conducted for the double-blind portion of these studies. Log-transformed standardized seizure frequency per 4 weeks over the 12-week maintenance period was analyzed using ANCOVA model with fixed effects for treatment, study, baseline standardized seizure frequency and number of con-AEDs, and interaction of treatment with the 4 most commonly used con-AEDs. Results: The most commonly used con-AEDs were carbamazepine (58.7%), lamotrigine (23.5%), valproic acid (23.5%), and topiramate (16.7%). ESL 800 and 1200 mg QD significantly reduced seizure frequency compared to placebo. There was no significant interaction between type of con-AED and treatment effect. Conclusions: Adjunct treatment with ESL 800 and 1200 mg QD had a consistent effect in reducing seizure frequency compared to placebo independent of type of con-AEDs. The limitation of these analyses was that patients may have been on more than a single con-AED and the impact of these combinations could not be assessed. Supported by: BIAL-Portela & Ca, SA. Data analysis and editorial support provided by Sunovion Pharmaceuticals, Inc., Marlborough, MA. Disclosure: Dr. Versavel has received personal compensation for activities with Sunovion Pharmaceuticals Inc. as an employee. Dr. Cheng has received personal compensation for activities with Sunovion Pharmaceuticals, Inc. Dr. Blum has received personal compensation for activities with Sunovion Pharmaceuticals Inc as an emplyee. Dr. Blum holds stock and/or stock options in GlaxoSmithKline, which sponosred research in which Dr. Blum was involved as an investigator. Ms. Zummo has received personal compensation for activities with Sunovion Pharmaceuticals Inc. Dr. Nunes has received personal compensation for activities with BIAL as an employee. Dr. Soares da Silva has received personal compensaiton for activities with Bial-Portela & Co., S.A. as an employee.