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Background Patient satisfaction with treatment in relapsing-remitting multiple sclerosis (RRMS) has a direct impact on adherence to treatment and, consequently, upon treatment outcomes and costs. Patient-reported outcomes (PROs) are a common method for determining patient satisfaction in MS and other diseases. Methods The 12-month, open-label, Phase IV CONFIDENCE study assessed patient satisfaction and treatment adherence, using PROs, as well as safety outcomes in patients with RRMS treated with glatiramer acetate (GA). In the previously reported (Cutter et al., 2019) initial 6-month core phase of the study, patients were randomized to receive three-times-weekly (TIW) GA 40 mg/mL (GA40; n = 431) or once-daily GA 20 mg/mL (GA20; n = 430). In the 6-month, single-arm extension phase, 789 patients completing the core phase were treated with GA40 to determine whether benefits observed in the core phase were sustained during the extension phase, to ascertain if switching from GA20 to GA40 resulted in PRO changes, and to assess safety outcomes. Results Superior PRO scores for patient satisfaction with treatment, patient perception of treatment convenience, and symptomatic changes (fatigue impact and mental health) observed in the GA40 group versus the GA20 group in the core phase were all maintained in the extension phase. Treatment adherence, significantly greater in the GA40 versus the GA20 group in the core phase, was sustained in patients continuing to receive GA40 in the extension phase, while those who switched from GA20 to GA40 increased their adherence during the extension phase. Safety variables remained consistent throughout the study, with no notable changes observed in patients switching from GA20 to GA40. Conclusions Data from the extension phase of the CONFIDENCE study show that the benefits associated with GA40 treatment in terms of medication satisfaction, treatment convenience perception, symptomatic changes in fatigue impact and mental health status, and treatment adherence were maintained over a 12-month observation period. These results confirm the preferential utility of GA40 versus GA20 in clinical practice, with no additional safety concerns associated with switching from GA20 to GA40.

Background Patients who perceive their medication to be ineffective or inconvenient are less likely to be adherent to treatment, with potentially significant consequences on long-term clinical outcomes. Many patients with multiple sclerosis (MS) are nonadherent to treatment despite demonstrated efficacy of disease-modifying therapies (DMTs). While glatiramer acetate (GA; Copaxone®, Teva Pharmaceuticals) both 20 mg/mL once daily (GA20) and 40 mg/mL three times weekly (GA40) have demonstrated efficacy in relapsing-remitting MS (RRMS), GA40 has a superior tolerability profile in addition to a more convenient dosing schedule. These characteristics may give rise to greater treatment satisfaction and higher rates of adherence with potentially beneficial effects on clinical outcomes and health-related costs. Methods CONFIDENCE was a Phase 4, interventional, open-label, randomized, 2-arm, parallel-group, global study with a duration of 6 months. Patients (N = 861) were randomly assigned 1:1 to receive GA20 (n = 430) or GA40 (n = 431) during the core phase. The primary endpoint was patient-reported medication satisfaction using the Medication Satisfaction Questionnaire (MSQ). Secondary endpoints included self-reported convenience perception using the Treatment Satisfaction Questionnaire for Medication-9 convenience component, symptomatic changes (Modified Fatigue Impact Scale, MFIS), and Mental Health Inventory (MHI). Treatment adherence was measured by Multiple Sclerosis Treatment Adherence Questionnaire. Results from the core phase were included. Results During the core phase, 857 patients received treatments. Patients on GA40 were statistically significantly more satisfied with their medication than those on GA20 (LSM difference in MSQ, 0.3; 95% CI, 0.2, 0.5; p Conclusions Higher levels of satisfaction, perception of convenience, and adherence were reported by patients on GA40 than those on GA20. Clinical trial registration number This trial was registered with ClinicalTrials.gov (NCT02499900).

Background: Appropriate counseling and treatment for women with multiple sclerosis (MS) who may become pregnant requires an understanding of the effects of exposure to disease-modifying therapies (DMTs) during pregnancy. Current reports and studies are limited in their usefulness, mostly by small sample size. Branded glatiramer acetate (GA) is a DMT approved for the treatment of relapsing forms of MS. For more than 2 decades, it has been shown to be efficacious and to have a favorable safety profile. The Teva Pharmaceutical Industries Ltd global pharmacovigilance database comprises data from more than 7000 pregnancies, during which women with MS were exposed to treatment with branded GA. Methods: We analyzed data from Teva's global pharmacovigilance database. Pregnancy outcomes for patients treated with branded GA were compared with reference rates of abnormal pregnancy outcomes reported in two large registries representing the general population. Results: Pregnancies exposed to branded GA were not at higher risk for congenital anomalies than what is expected in the general population. Conclusions: These data provide evidence that branded GA exposure during pregnancy seems safe, without teratogenic effect.

Background Fingolimod is a once-daily, oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing multiple sclerosis. Objective This post-hoc analysis of phase 3 FREEDOMS data assessed whether the effects of fingolimod are consistent among subgroups of patients defined by prior treatment history. Methods Annualized relapse rate and safety profile of treatment with fingolimod 0.5 mg, 1.25 mg, or placebo once-daily for 24 months were analyzed in 1272 relapsing multiple sclerosis patients, by subgroups based on disease-modifying therapy history (treatment-naive; prior interferon-β or glatiramer acetate), reason for discontinuation of prior disease-modifying therapy (unsatisfactory therapeutic response or adverse events), and prior disease-modifying therapy duration. Results Both fingolimod doses significantly reduced annualized relapse rate in patients that received prior interferon-β or glatiramer acetate, discontinued prior disease-modifying therapy owing to unsatisfactory therapeutic effect, were treatment-naive, or had prior disease-modifying therapy duration of >1–3 years (P≤0.0301 for all comparisons vs placebo). Fingolimod 1.25 mg resulted in greater reductions in annualized relapse rate in patients that discontinued prior disease-modifying therapy for adverse events or had prior disease-modifying therapy duration of ≤1 year or >3 years (P≤0.0194 vs placebo). Conclusions Fingolimod demonstrated similar efficacy in relapsing multiple sclerosis patients regardless of prior treatment history. Clinicaltrials.gov identifier: NCT00289978.

Patient-reported outcomes, including treatment satisfaction, are now recognized as important and valid measures in assessment of therapeutic interventions. This randomized, 6-week, prospective, blinded-initiation study evaluated medication satisfaction as a primary outcome measure in a schizophrenia trial. Participants with suboptimal response to oral risperidone were randomized to paliperidone extended release (ER) immediate or delayed (week 2) initiation. Primary endpoint was change in Medication Satisfaction Questionnaire (MSQ; ratings from 1=extremely dissatisfied to 7=extremely satisfied) score at endpoint (last observation carried forward) for the overall population (all randomized participants). In total, 201 participants were randomized to immediate (n=100) or delayed (n=101) initiation of paliperidone ER. In the overall population, the mean + or - standard deviation MSQ score improved from 2.7 + or - 0.8 (very to somewhat dissatisfied) at baseline to 5.1 + or - 1.2 (somewhat satisfied) at endpoint (P0.001). On the basis of dichotomized analysis of the MSQ scale (score 1-4=dissatisfied, 5-7=satisfied), 82.7% of participants were satisfied with their medication at endpoint. At the 2-week time point, significantly more participants in the immediate initiation group reported satisfaction (67.7%) compared with those in the delayed initiation group (45.3%) (P=0.002), who were still receiving risperidone at this time. Positive And Negative Syndrome Scale total scores also improved from baseline to endpoint (-12.9 + or - 13.1; P0.001). Most common adverse events were insomnia (9.1%), constipation (7.6%), headache (7.6%) and somnolence (6.6%). Participants with schizophrenia who were suboptimally responsive to risperidone reported improved medication satisfaction after initiation of paliperidone ER.

Glatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GA’s biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line. Consistent with previous literature, branded GA upregulated anti-inflammatory markers (e.g. IL10) and modulated multiple immune-related pathways. Despite some similarities, significant differences were observed between expression profiles induced by branded GA and Probioglat, a differently-manufactured glatiramoid purported to be a generic GA. Key results were verified using qRT-PCR. Genes (e.g. CCL5, adj. p −5) critically involved in pro-inflammatory pathways (e.g. response to lipopolysaccharide, adj. p = 8.7 × 10−4) were significantly induced by Probioglat compared with branded GA. Key genes were also tested and confirmed at the protein level and in primary human monocytes. These observations suggest differential biological impact by the two glatiramoids and warrant further investigation.

Summary: Purpose: To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs). Methods: Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method. Results: TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 ± 34.0 ml/h/kg) than in those receiving VPA (49.6 ± 13.6 ml/h/kg) or neutral AEDs (46.5 ± 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0–12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs. Conclusions: Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.

Objective: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs).Background: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery.Design: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30–46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing.Methods: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled.Results: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a ≥50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported ≥1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC.Conclusion: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

Background Fingolimod demonstrated superior efficacy compared with interferon β-1a intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. Objectives This post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. Methods Annualized relapse rate and safety of once-daily oral fingolimod 0.5mg, 1.25mg, or once-weekly interferon β-1a 30μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. Results Compared with interferon β-1a intramuscular, fingolimod 0.5mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of ≥1 year ( P≤ 0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25mg for treatment-naive and prior interferon-β-treated patients. Conclusions This analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials.gov identifier: NCT00340834.

Approved symptomatic therapies for Alzheimer's disease (AD) provide modest relief. In the future, it is likely that symptomatic treatments will be utilized with AD modifying therapies, the development of which are currently a primary focus of research. The nicotinic α7 receptor agonist may be an attractive drug candidate to potentially improve cognition in Alzheimer's disease patients either as a stand-alone therapy or in combination with other symptomatic treatments. EVP-6124 is a novel, potent, and selective α7 nicotinic receptor agonist. EVP-6124 has an excellent brain to plasma exposure ratio and has shown excellent efficacy and potency in a number of animal models of cognition. Four clinical studies in >125 healthy normal human subjects have been completed with EVP-6124, including a single-ascending-dose study, a 14-day multiple-ascending-dose study, a 21-day multiple-dose study, and a single-dose relative bioavailability, food, and gender effect study. EVP-6124 exhibited linear kinetics over the range of 1 to 180 mg and demonstrated a half-life suitable for once daily dosing. EVP-6124 appears to be safe and well tolerated for up to 21 days as measured by adverse events, vital signs, continuous cardiac monitoring, physical examination, and clinical laboratory evaluations. In addition, in normal volunteers, EVP-6124 demonstrated pro-cognitive effects (CogState testing) in various cognitive domains including executive function. These data suggest that EVP-6124 administered to AD subjects on stable cholinesterase inhibitor therapies may have potential benefit and that further study in this patient population is indicated. Larger phase II studies are currently being initiated in both Alzheimer's disease and schizophrenia.

The Medication Satisfaction Questionnaire (MSQ) is a single-item questionnaire which evaluates satisfaction with antipsychotic medication in schizophrenia patients. This study evaluated the reliability and validity for its use in research and clinical settings. Data pooled across treatment groups (control vs. Paliperidone ER) from a randomized 6-week study were used to conduct four psychometric assessments of the MSQ: (1) test-retest reliability, (2) convergent validity, (3) known-groups validity, and (4) minimally important difference (MID). This analysis included 191 randomized subjects. Test-retest reliability was evaluated for patients with no change in satisfaction from weeks 2 to 4 and weeks 4 to 6 (ICC=0.80; 0.83, respectively). Convergent validity was demonstrated through large correlations with Treatment Satisfaction Questionnaire for Medication (TSQM) global score (r=0.72-0.77), and through small correlations with variables measuring clinical symptoms and functioning (e.g., Positive and Negative Syndrome Scale (PANSS) total score [r=-0.30 to -0.17], CGI-S [r=-0.35 to -0.27], SF-36 Physical Functioning Score [r=0.18] and side effects and extrapiramidal measures (including UKU, ESRS-A, SAS). Mean MSQ scores were significantly different between those who completed and discontinued the study, and between different satisfaction groups based on TSQM, demonstrating good known-groups validity. MID estimates for the MSQ ranged from 0.47 (standard error of measurement) to 0.58 (anchor-based method). Results suggest that the MSQ has acceptable reliability and validity, making this single-item questionnaire appropriate and easy to use in clinical research and potentially in clinical practice. A 1-point change on the MSQ may be considered clinically meaningful.

A double-blind, dose-controlled study evaluated topiramate as monotherapy in 470 patients with newly diagnosed (≤ 3 months) epilepsy or epilepsy relapse in the absence of therapy. In addition to having at least 2 lifetime-unprovoked seizures, patients had 1 or 2 partial-onset seizures or generalized-onset tonic-clonic seizures during a 3-month retrospective baseline. The trial included a large cohort (N = 151, 32%) of children and adolescents 6 to 15 years of age. Eligible patients were randomized to treatment groups in which topiramate was titrated to target maintenance dosages of either 400 mg/day (n = 77) or 50 mg/day (n = 74). Patients were followed for at least 6 months. Based on Kaplan-Meier analyses, the primary efficacy endpoint of time to first seizure favored the higher topiramate dose in both the overall population and the cohort of children/adolescents. The probability that children/adolescents remaining in the study were seizure free at 6 months was 78% in the 50-mg target dose group and 90% with the higher dose. At 12 months, the probability of being seizure free was 62% and 85%, respectively. The incidence of treatment-limiting adverse events was 4% in the 50-mg target dose group and 14% in the group assigned to 400 mg as a target dose. The most common adverse events, excluding typical childhood illnesses, were headache, appetite decrease, weight loss, somnolence, dizziness, concentration/attention difficulty, and paresthesia. As shown in this subset analysis, topiramate is effective and well tolerated as monotherapy in children and adolescents.

Introduction International guidelines recommend assessing the overall long-term benefit of antiepileptic drugs (AEDs) using multidimensional measures. Effectiveness encompasses the effects of a product's efficacy, safety, and tolerability. Retention reflects effectiveness over time. This double-blind study (NCT00563459) was designed to compare the 6- and 12-month retention (as the primary parameter) of patients taking carisbamate (the investigational drug), topiramate, and levetiracetam when used as adjunctive treatment for partial onset seizures (POS). The retention hypotheses were that carisbamate would be at least as good as each comparator. Additionally, because cognitive and neuropsychiatric adverse events (AEs) have an impact on acceptance of therapy, the incidences of these AEs were assessed with the hypotheses that carisbamate would be superior to topiramate on cognitive AEs and superior to levetiracetam on neuropsychiatric AEs. The aforementioned hypotheses were analyzed using a fixed-sequence testing procedure. Methods Following a screening phase, ∼600 adult patients with POS and a history of inadequate response to treatment with e1AED had to be randomized in a 1:1:1 ratio to enter a 7-week titration period. Target daily doses of study medications were carisbamate 800 mg/day, topiramate 300 mg/day or levetiracetam 2000 mg/day, (dose adjustment could be done within the limits of 400–1200 mg/day; 200–400 mg/day; or 1000–3000 mg/day, respectively). After titration, patients entered the 17-week maintenance period. The 7-week titration and 17-week maintenance phases comprise the 6-month (24-week) core double-blind phase, with an option for an additional 6-month double-blind extension phase. The primary endpoint was the time from the first intake of study medication to any cause of discontinuation over the 6-month core double-blind phase. Cognitive AEs, neuropsychiatric AEs, reasons for discontinuation, seizure rates, cognitive changes relative to baseline assessed with a computerized cognitive test battery, and patient-reported mood states, behavioral, and cognitive changes relative to baseline using the Profiles of Mood Status questionnaire, Center for Epidemiologic Studies Depression Scale, and patient- and observer-reported Overall Mental Effects Questionnaire among the 3 treatment arms were assessed at 6- and 12-months post-randomization. This study design can provide unique information and meaningful data that might be valuable for clinical decision-making. Support Support was provided by Johnson & Johnson Pharmaceutical Research & Development , LLC.