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Introduction Antiepileptic drugs AEDs are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service NHS use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide. Methods and analysis This is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to month remission from seizures. Secondary outcomes include time to treatment failure including due to inadequate seizure control or unacceptable adverse reactions ; time to first seizure; time to month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED. The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement. This is an open access article distributed in accordance with the Creative Commons Attribution 4. You will be able to get a quick price and instant permission to reuse the content in many different ways. The study is adequately powered to examine the clinical effectiveness of standard and new antiepileptic drugs AEDs. This is a long-term trial that will provide evidence of the long-term effects of some AEDs. A further limitation is the reliance on patient completed questionnaires, which should be offset by access to hospital episode statistic data. It is uniquely stigmatising and has a negative impact on quality of life QoL and employment prospects. The ultimate goal of treatment is to maximise QoL by eliminating seizures at drug doses that do not cause side effects. However, for many patients, there is a necessary trade-off between effective seizure control and side effects, which can diminish QoL. Over the past 20 years, a number of new drugs have become available for the treatment of epilepsy. These new drugs have been approved for National Health Service NHS use on the basis of information from short-term trials. These trials do not provide information about the longer term outcomes, which inform decisions made by doctors and patients, nor do they provide any useful health economic data to inform policy. The standard and new antiepileptic drugs SANAD-I trial began in and compared the effectiveness and cost-effectiveness of standard and new treatments that were available at that time. Since SANAD-I, a number of newer treatments have become available, the most promising of that are levetiracetam and zonisamide. While the focal epilepsies are further classified into a number of syndromes 6 largely according to aetiology and site of onset, it has been common practice to recruit a heterogeneous population with focal onset seizures into epilepsy trials. There are currently no reliable data that indicate whether relative treatment responses differ among the focal epilepsies, indeed prognostic modelling of data from SANAD-I suggests that treatment effects are consistent across focal epilepsy syndromes as currently classified. Levetiracetam is a commonly used AED with evidence for efficacy non-inferiority NI to carbamazepine for 6-month seizure remission as monotherapy in focal epilepsy from regulatory studies with too short a duration of follow-up to inform policy. Zonisamide is a drug that has been available for many years in Japan and other countries in South East Asia where it is commonly used both as initial monotherapy and as an add-on treatment and is licensed for use in the European Union and USA. Evidence for efficacy is from industry-sponsored regulatory studies demonstrating NI when compared with carbamazepine for 6-month seizure remission rates. Arm B generalised or unclassified epilepsy of SANAD-II will compare levetiracetam and valproate in patients with generalised onset seizures or seizures that are difficult to classify. Generalised onset seizures represent a group of syndromes, most of which are currently classified as one of the idiopathic generalised epilepsies, 6 which are largely classified according to seizure type and age of onset. While differing syndromes are recognised, there is currently no reliable evidence that relative treatment responses differ among syndromes, indeed prognostic modelling of data from SANAD-I indicates that relative treatment responses are consistent across syndromes. As in SANAD-I, patients enter Arm B of the trial based on a classification of seizures generalised onset or difficult to classify , with patients further classified by syndrome where and when such a syndromic diagnosis can be made. Few RCTs have been undertaken to assess the comparative effects of AEDs in patients with generalised onset seizures or in those with seizures who are difficult to classify, even though these individuals represent over one-third of people with epilepsy. Valproate has for some time been recommended as a first-line treatment for such patients 11 but without evidence from RCTs to support this recommendation. Cochrane reviews have compared valproate with other AEDs, 12 13 but due to problems with power and epilepsy classification, none has shown an advantage for valproate. Also, a double-blind trial of 16 weeks therapy in childhood and juvenile absence epilepsy, 14 valproate and ethosuximide were significantly superior to lamotrigine for the outcome treatment failure. Time to treatment failure due to inadequate seizure control. Time to treatment failure due to unacceptable adverse events. This event will have occurred when the patient experiences adverse events attributed to the drug necessitating its withdrawal. Health economic outcomes expressed as the incremental cost per quality-adjusted life-year QALY gained. Arm A of the trial recruits participants diagnosed with focal epilepsy and arm B—with generalised or unclassified epilepsy. Trial participants are randomised to an AED within each arm. In arm A, the control treatment is lamotrigine and the new treatments are levetiracetam and zonisamide, in treatment group ratio of In arm B, the new treatment levetiracetam is compared with the control treatment valproate in treatment group ratio of The sample size for the trial is participants with focal epilepsy and with generalised or unclassified epilepsy. All patients meeting the eligibility criteria table 1 will be invited to participate in the study and provided with an age and development-appropriate patient information sheet and consent form. Patients will be allowed sufficient time to discuss trial and to decide on their participation. Once consent has been obtained, the baseline data will be collected and patient will be progressed to randomisation. The arm A or B to which the patient is assigned will be decided by the recruiting physician based on their epilepsy classification. Patients will then be randomised to one of the following treatments: to lamotrigine, levetiracetam or zonisamide in arm A or to levetiracetam or valproate in arm B. Randomisation will use a minimisation programme with a built-in random element using factors that will not be made known to individuals in charge of recruitment to minimise any potential for predicting allocation. Randomised treatment should begin within 7 days of randomisation. The research team should ensure that the duration between obtaining consent, performing baseline assessments, randomisation and the start of trial treatment does not impact on the well-being of the participant. All treatments will be taken as formulations already licensed to be used in UK and there will be no modifications made to the products or their outer packaging. All treatments will be prescribed as per routine NHS practice and dispensed by hospital and community pharmacies as they would normally be. It is accepted that, for a variety of reasons including perceived or actual efficacy and tolerability, not all patients will take their medicines as prescribed. Patients will be asked about adherence in the QoL questionnaires, but no objective measurements of adherence are planned nor will the primary analyses be adjusted for actual or estimated adherence. All patients will be titrated to an initial maintenance dose, with dose adjustments made at subsequent appointments according to the clinical response and adverse effects. Guidelines for titration and initial maintenance dose are provided within the protocol table 2 , however, clinicians will be able to alter this to choose the titration rate and initial maintenance they think most appropriate for individual patients. The aim of treatment will be to control seizures with a minimum effective dose of drug. This will necessitate dosage modification dose increased or reduced if further seizures or adverse events occur as is usual clinical practice. Any changes in medication must be documented along with the justification for those changes. At the end of trial participation, the participants may continue their treatment as per local policy. To avoid potentially confounding issues, ideally patients should not be recruited into other epilepsy trials. Patients were recruited over a 4. The maximum time that a patient will receive their randomised treatment is 6. Table 3 shows the schedule of follow-up. All participants will be followed up whether they are still taking their allocated treatment or not. Where patients default from clinic follow-up, additional information will be sought from general practitioners who will be the main prescribers of AEDs in this trial. Patients will be followed up as per routine clinical practice and typically at 3, 6 and 12 months and annually thereafter. Patients may be seen at other times as clinically indicated. Where treatment is stopped, the participant will be asked to continue with the trial follow-up and to attend the follow-up visits. Efficacy of the trial treatments will be measured throughout the trial using a number of measures. Data on seizures will provide a subjective measure of efficacy. QoL data obtained throughout the trial using age-appropriate questionnaire booklets table 4 can be used as a subjective measure of efficacy. The currently recommended approach of using parental proxy reports of QoL for this age group will be used. Direct costs of healthcare resources used by patients in the trial will be collected in three ways:. Downloaded Healthcare Resource Group data will include information on outpatient epilepsy, general neurology and paediatric clinics visits; accident and emergency attendance and length and nature of hospitalisations. Resources triggered by ARs will be captured in the follow-up case report form CRF for each patient experiencing a serious AR requiring hospitalisation. Because of potential issues related to completeness of routine data, these will be used to compliment HES data. Unit costs will be taken from the NHS reference costs database 25 and other appropriate sources. Whole blood or saliva samples will be shipped to a central laboratory at The University of Liverpool for extraction and storage. Samples will instead be genotyped in future projects and data arising from that analysis included in international epilepsy genomics initiatives. Identification of genetic factors associated with response to treatment in epilepsy is important and may ultimately help to optimise efficacy, tolerability and safety of AEDs. A new drug might become a standard first-line treatment if it is proven to be non-inferior for efficacy but superior for tolerability when compared with a standard treatment—tolerability is examined in secondary outcomes including time to treatment failure for adverse effects. Powering the study for NI will also provide sufficient power to detect important differences between treatment policies. No empirical work has yet been undertaken to underpin the choice of equivalence or NI margins in epilepsy trials. Calculations have been informed by the SANAD-I study, which estimated the month remission-free probability at 24 months as 0. The calculations assume a HR of 1. For patients with focal-onset seizures arm A , two primary comparisons are of interest levetiracetam vs lamotrigine and zonisamide vs lamotrigine , therefore, the one-sided significance level has been divided by two one-side alpha 0. For patients with generalised-onset seizures or seizures that are difficult to classify arm B , there is only one comparison of interest levetiracetam vs valproate. Therefore, with a one-sided alpha of 0. The total number of patients required is All primary analyses will be on an intention to treat ITT basis including all randomised patients retained in their randomised treatment groups. Separate analyses will be undertaken for each randomisation arm. The interval in days from randomisation to occurrence of a month remission will be summarised by Kaplan-Meier curves for each treatment group. Survival regression models will be explored; two different models will be used: 1 including the treatment effect only using treatment indicator variables and 2 including the treatment effect together with covariates. The impact of centre effect on the treatment comparison will be investigated using both fixed and random effect models. A per protocol analysis will be undertaken to assess the robustness of ITT analyses. A similar analysis strategy will be employed for the other secondary time to event outcomes. For time to treatment failure, further analysis will be undertaken to assess the two main reasons for treatment failure—inadequate seizure control and unacceptable adverse effects. To allow for possible dependence between the different withdrawal risks, cumulative incidence analyses will be presented. The Haybittle-Peto approach will be employed for each interim analysis, with The final analysis will be undertaken at the end of the trial when all patients have a minimum 2-year follow-up data 6. QoL data will be analysed longitudinally to explore between treatment changes in scale scores over time, taking account of baseline QoL. For the analysis of ARs, all patients who received any amount of each study drug will be included in the safety analysis dataset in the treatment group they actually received. All ARs and serious ARs reported by the clinical investigators will be presented, identified by treatment group. ARs will be grouped according to a prespecified coding system and tabulated. The number and percentage of patients experiencing each AR, and the number and percentage of occurrences of each AR will be presented. No formal statistical testing will be undertaken. For the health economic analyses, the perspective of the NHS and Personal Social Services will be adopted for costing purposes. It will be assessed whether levetiracetam or zonisamide as monotherapy in newly treated focal epilepsy is cost-effective by estimating the incremental cost-utility and cost-effectiveness ratios relative to lamotrigine and to each other. The same approach will be used to compare levetiracetam and valproate for generalised-onset seizures. A cost consequence analysis 30 will be conducted to consider non-health benefits that are neither captured within the QALY calculation, nor in the cost-effectiveness analyses. Sensitivity analyses will be conducted to test the robustness of our findings. These analyses will be based on the observed distributions of outcome and costs to test whether, and to what extent, the incremental cost-utility and cost-effectiveness ratios are sensitive to key assumptions in the analysis. Uncertainty in parameter estimates will be addressed through the application of bootstrapping and the estimation of cost-effectiveness acceptability curves. The estimated incremental cost per QALY will be compared with the threshold for cost-effectiveness operating in the UK, and the incremental cost per seizure will be avoided and per month remission will be compared with the results of other economic assessments of AEDs. The trial protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines. Participating centres will be expected to each maintain a file of essential trial documentation Site File , which will be provided by the coordinating centre and keep copies of all completed CRFs. Data collection will use paper CRFs and participant completed questionnaires. Trial Oversight Committees have been formed in relation to the monitoring. This includes an Independent Data and Safety Monitoring Committee IDSMC , consisting of independent epilepsy experts and statisticians; A Trial Management Group TMG consisting of the chief investigator, trial manager, trial statisticians, sponsor representatives, several principal investigators and a Trial Steering Committee TSC consisting of two independent epilepsy clinicians, an independent statistician and a lay representative, in addition to select members of the TMG. Trial monitoring is informed by a risk assessment to determine the level and type of monitoring required for specific hazards. The study opened to recruitment in and completed recruitment in June Participants are followed up for a minimum of 2 years and a maximum of 6. Follow-up visits and data collection will continue until June We would like to acknowledge the input of the wider SANAD-II team and to thank the research sites and participants for being involved in this study. We would like to specifically thank Epilepsy Action for their invaluable contribution throughout the trial. All authors were able to contribute to the draft and approved the final text. Refer to the Methods section for further details. Provenance and peer review Not commissioned; externally peer reviewed. Skip to main content. Log In More Log in via Institution. Log in via OpenAthens. Log in using your username and password For personal accounts OR managers of institutional accounts. Forgot your log in details? Register a new account? Forgot your user name or password? Search for this keyword. Advanced search. Latest content Archive For authors About Browse by collection. Log in via Institution. You are here Home Archive Volume 10, Issue 8 Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs SANAD-II. Email alerts. Article Text. Article menu. Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs SANAD-II. Statistics from Altmetric. The study is adequately powered to examine the cost-effectiveness of standard and AEDs. A limitation is that the study is not blinded. Arm B Arm B generalised or unclassified epilepsy of SANAD-II will compare levetiracetam and valproate in patients with generalised onset seizures or seizures that are difficult to classify. Trial outcomes Primary outcome The primary outcome of the trial is time to month remission from seizures. Secondary outcomes The secondary outcomes are Time to treatment failure. Time to first seizure. Time to month remission. Adverse reactions ARs. Enrolment and randomisation Screening and baseline The SANAD-II trial will take place in NHS outpatient epilepsy, general neurology and paediatric epilepsy and general clinics in the UK a full list of participating sites is available from the trial website. View this table: View inline View popup. Table 1 Eligibility criteria. Randomisation The arm A or B to which the patient is assigned will be decided by the recruiting physician based on their epilepsy classification. Table 2 Titration and initial maintenance dose. Assessments and procedures Schedule for follow-up Patients were recruited over a 4. Table 3 Schedule of follow-up. Table 4 Age-appropriate questionnaire booklets. Statistical analysis All primary analyses will be on an intention to treat ITT basis including all randomised patients retained in their randomised treatment groups. Health economic evaluation For the health economic analyses, the perspective of the NHS and Personal Social Services will be adopted for costing purposes. Ethics and dissemination Ethics The trial protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines. Trial monitoring Trial Oversight Committees have been formed in relation to the monitoring. Time frame and trial status The study opened to recruitment in and completed recruitment in June Acknowledgments We would like to acknowledge the input of the wider SANAD-II team and to thank the research sites and participants for being involved in this study. Epilepsy: frequency, causes and consequences. New York : Demos Publications , Labor market participation following onset of seizures and early epilepsy: findings from a UK cohort. Epilepsia ; 50 : — 9. Schachter SC. Quality of life for patients with epilepsy is determined by more than seizure control: the role of psychosocial factors. Expert Rev Neurother ; 6 : — 8. OpenUrl PubMed. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet ; : — The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia ; 30 : — Developing a prognostic model for epilepsy data. Montpellier : ISCB , Levetiracetam monotherapy study G comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology ; 68 : — 8. KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry ; 84 : — Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol ; 11 : — National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care , Carbamazepine versus valproate monotherapy for epilepsy. Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK epilepsy and pregnancy register. J Neurol Neurosurg Psychiatry ; 77 : — 8. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med ; : — New measures to avoid valproate exposure in pregnancy endorsed: member state representatives agree new restrictions and pregnancy prevention programme , Measuring the impact of epilepsy: the development of a novel scale. Epilepsy Res ; 16 : 83 — 8. Ravens-Sieberer U , Bullinger M. Assessing health-related quality of life in chronically ill children with the German KINDL: first psychometric and content analytical results. Qual Life Res ; 7 : — Epilepsia ; 40 : — Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health. Pediatrics ; : e — Measuring health preferences for use in cost-utility and cost-benefit analyses of interventions in children: theoretical and methodological considerations. Pharmacoeconomics ; 25 : — Epilepsia ; 41 : — Beecham JKM. Costing psychiatric interventions. In : Measuring mental health needs. London : Gaskell , : — BMJ group and pharmaceutical press , Curtis LA. Unit costs of health and social care Canterbury : University of Kent , Chadwick D. Considerations on designing clinical trials to evaluate the place of new antiepileptic drugs in the treatment of newly diagnosed and chronic patients with epilepsy. Epilepsia ; 39 : — Importance of competing risks in the analysis of anti-epileptic drug failure. Trials ; 8 : The role of cost-consequence analysis in healthcare decision-making. Pharmacoeconomics ; 13 : — The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review. Health Technol Assess ; 10 doi Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess ; 9 : 1 — Ann Intern Med ; : — 7. Competing interests None declared. Patient consent for publication Not required. Read the full text or download the PDF:. Log in.

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Many people with epilepsy continue to experience seizures despite the use of daily medications anti-epileptic drugs. Heritage and Innovation come together in a reliable nasal spray. Learn about the many advantages our proprietary technology offers people with neurological conditions. Find out more. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. A second dose should not be given if there is concern about the person's breathing, they need help with their breathing, or have extreme drowsiness. Call your healthcare provider for medical advice about side effects. You may report side effects to Neurelis, Inc. Please see full Prescribing Information and Medication Guide for additional important safety information. References: 1. Neurelis, Inc. Seizure cluster: definition, prevalence, consequences, and management. Active epilepsy and seizure control in adults— United States, and National Institute of Neurological Disorders and Stroke. The epilepsies and seizures: hope through research. NIH publication Published April Updated August 8, Accessed January 24, Manford M. Recent advances in epilepsy. J Neurol. Use of an online epilepsy diary to characterize repetitive seizures. Epilepsy Behav. Epilepsy Foundation Greater Chicago. Status Epilepticus. Accessed July 9, Manno EM. Status epilepticus: current treatment strategies. Epilepsy Innovation Institute. Accessed July 3, Schulze-Bonhage A, Kuhn A. Unpredictability of seizures and the burden of epilepsy. Seizure Prediction in Epilepsy. KGaA; Sander JW. Eur J Neurol. PLoS One. Rescue therapies for seizure emergencies: new modes of administration. A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers. Epilepsy Res. Use of diazepam in treatment of severe status epilepticus. Br Med J. Maggio ET. Intravail: highly effective intranasal delivery of peptide and protein drugs. Expert Opin Drug Deliv. You are now leaving the Neurelis. Neurelis takes no responsibility for, and exercises no control over, the organizations, views, or accuracy of the information contained on third-party sites or servers. You are about to enter a site containing information on Medical Affairs and Research that is intended for US healthcare professionals only. Please confirm you are a healthcare professional and you wish to proceed to the HCP-only site. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription drugs, or street drugs. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system CNS depressants including street drugs can cause severe drowsiness, breathing problems respiratory depression , coma, and death. 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