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Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

ABSTRACT: To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome.Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg-1·d-1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg-1·d-1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ?40% and increasing seizure rates.Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ?75% responders demonstrated a consistent response over time. Few patients had a dosage increase ?40% associated with an increase in seizure rates.Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated.NCT00518713 and NCT01160770.This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment.

SUBMITTER: Gidal BE

PROVIDER: S-EPMC5089527 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

Gidal Barry E BE Wechsler Robert T RT Sankar Raman R Montouris Georgia D GD White H Steve HS Cloyd James C JC Kane Mary Clare MC Peng Guangbin G Tworek David M DM Shen Vivienne V Isojarvi Jouko J

Neurology 20160928 17

<h4>Objective</h4>To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome.<h4>Methods</h4>Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg<sup>-1</sup>·d<sup>-1</sup> clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg· ...[more]

PMID: 27683846

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Project description:IntroductionA post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.MethodsIn the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.ResultsIn the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.ConclusionLurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.Trial registrationClinicalTrials.gov identifier NCT00641745.

Project description:ObjectiveTo report long-term post hoc efficacy and safety data from 10 US study sites from an open-label Phase 3 study of adjunctive cenobamate (NCT02535091).MethodsPatients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019.ResultsOf 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1-4 (12.5-25 mg/day cenobamate) and 61.7% during Weeks 5-8 (50-100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12-month duration of 100% seizure reduction. Common treatment-emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).SignificanceThis post hoc analysis of a subset of patients from the long-term open-label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.

Project description:IntroductionThe DYSCOVER study was a phase 3b, open-label, randomized trial (NCT02799381) that evaluated levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) in patients with Parkinson's disease (PD) and a high burden of dyskinesia at baseline (defined as Unified Dyskinesia Rating Scale [UDysRS] total score ≥ 30). At week 12, patients receiving LCIG versus OMT experienced significant improvements in dyskinesia, pain, and health-related outcomes. The objective of this analysis was to examine correlations between dyskinesia, pain, and health-related outcomes in PD.MethodsThis post hoc analysis assessed correlations between UDysRS, King's Parkinson's Disease Pain Scale (KPPS), 8-item Parkinson's Disease Questionnaire (PDQ-8), Unified Parkinson's Disease Rating Scale part II, Clinical Global Impression of Severity (CGI-S) or Change (CGI-C), and "On" time without troublesome dyskinesia at baseline and after 12 weeks of LCIG or OMT. Correlations were assessed by Pearson correlation coefficients (categorization: weak, r = 0.20-0.39; moderate, r = 0.40-0.59; strong, r ≥ 0.60).ResultsAmong 61 patients, moderate-to-strong positive and significant correlations were observed between UDysRS and KPPS scores (baseline, r = 0.47; week 12 change from baseline [CFB], r = 0.63; all p < 0.001). UDysRS and KPPS scores had moderate-to-strong positive and highly significant correlations with PDQ-8 scores (baseline, r = 0.45 and 0.46, respectively; CFB, r = 0.54 and 0.64, respectively; all p < 0.001). Moderate positive and significant correlations were observed between UDysRS and CGI-S/CGI-C scores (baseline, r = 0.41; CFB, r = 0.47; all p < 0.001).ConclusionsIn patients with high dyskinesia burden, positive correlations were observed between dyskinesia, pain, and health-related quality of life (HRQoL) at baseline. Improvements in dyskinesia and pain were associated with improvements in HRQoL, demonstrating the clinical burden of troublesome dyskinesia.Trial registration numberClinicaltrials.gov identifier NCT02799381.

Project description:Introduction/objectivesWe assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA).MethodsORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration.ResultsGenerally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p < 0.05) in Dose-up versus Stay-on 5 up to month 12. DAS28 remission rates were significantly greater in Dose-up versus Stay-on 5 at month 12. Change from baseline in DAS28 was similar in Dose-down and Stay-on 10. No significant differences in DAS28 LDA rates were observed between groups. Safety data were similar overall across the four groups.ConclusionIn patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety.Study registrationClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points • This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator's discretion, on efficacy and safety in patients with rheumatoid arthritis (RA). • Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy. • Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction. • These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.

Project description:BackgroundThe objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting.MethodsThis was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses.ResultsIn total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change - Migraine Headache Condition (56.5% vs 33.4%-52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%-83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency.ConclusionsBased on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018-001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018.

Project description:Baclofen, a racemic γ-aminobutyric acid B receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the γ-aminobutyric acid B receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets allow a dosing interval of 12 h and have shown a favourable safety and efficacy profile in early clinical development. A 12-week, randomized, placebo-controlled Phase 3 trial in adults with multiple sclerosis-related spasticity demonstrated that arbaclofen extended-release 40 mg/day significantly reduced spasticity symptoms compared with placebo and was safe and well tolerated. The current study is an open-label extension of the Phase 3 trial designed to evaluate the long-term safety and efficacy of arbaclofen extended-release. In a 52-week, open-label, multicentre study, adults with a Total Numeric-transformed Modified Ashworth Scale score ≥2 in the most affected limb received oral arbaclofen extended-release titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen extended-release safety and tolerability. Secondary objectives included an assessment of efficacy using the Total Numeric-transformed Modified Ashworth Scale-most affected limb, the Patient Global Impression of Change and Expanded Disability Status Scale. Of 323 patients enrolled, 218 (67.5%) completed 1 year of treatment. Most patients (74.0%) achieved an arbaclofen extended-release maintenance dose of 80 mg/day. At least one treatment-emergent adverse event was reported by 278 patients (86.1%). The most common adverse events were [n patients (%)]: urinary tract disorder [112 (34.7)], muscle weakness [77 (23.8)], asthenia [61 (18.9)], nausea [70 (21.7)], dizziness [52 (16.1)], somnolence [41 (12.7)], vomiting [29 (9.0)], headache [24 (7.4)] and gait disturbance [20 (6.2)]. Most adverse events were of mild-moderate severity. Twenty-eight serious adverse events were reported. One death occurred during the study, a myocardial infarction that was considered by investigators as unlikely to be related to treatment. Overall, 14.9% of patients discontinued due to adverse events, primarily muscle weakness, multiple sclerosis relapse, asthenia and nausea. Evidence of improvement in multiple sclerosis-related spasticity was observed across arbaclofen extended-release dosages. Arbaclofen extended-release treatment (up to 80 mg/day) was well tolerated and reduced symptoms of spasticity in adult patients with multiple sclerosis for 1 year. Clinical Trial Identifier: ClinicalTrials.gov, NCT03319732.

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Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

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Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

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