scholarly journals Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs

2021 ◽  
Vol 25 (75) ◽  
pp. 1-134
Author(s):  
Anthony G Marson ◽  
Girvan Burnside ◽  
Richard Appleton ◽  
Dave Smith ◽  
John Paul Leach ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Confidence Interval ◽  
Treatment Failure ◽  
Adverse Reactions ◽  
Focal Epilepsy ◽  
Clinical Effectiveness ◽  
Hazard Ratio ◽  
First Line ◽  
New Treatments ◽  
To Receive

Background Levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness. Objectives To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim®, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy. Design Two pragmatic randomised unblinded non-inferiority trials run in parallel. Setting Outpatient services in NHS hospitals throughout the UK. Participants Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication. Interventions Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program. Main outcome measures The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness. Results Focal epilepsy. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. Generalised and unclassifiable epilepsy. Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range –£587 to £1234) and less effective (incremental quality-adjusted life-year of –0.035, 95% central range –0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective. Limitations The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions. Future work SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel. Conclusions Focal epilepsy – The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. Generalised and unclassifiable epilepsy – The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate. Trial registration Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.

scholarly journals Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience

2019 ◽  
Vol 12 ◽  
pp. 175628641987351 ◽  
Author(s):  
Bernhard J. Steinhoff ◽  
Anke M. Staack
Keyword(s):  
Antiepileptic Drug ◽  
Adverse Reactions ◽  
Focal Epilepsy ◽  
Receptor Site ◽  
Pharmacokinetic Profile ◽  
Behavioral Symptoms ◽  
Controlled Trials ◽  
First Line ◽  
Tertiary Referral ◽  
Randomized Controlled

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 88-88
Author(s):  
Kazumasa Fujitani ◽  
Hiroya Takiuchi ◽  
Naotoshi Sugimoto ◽  
Hiroshi Imamura ◽  
Shohei Iijima ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Confidence Interval ◽  
Locally Advanced ◽  
Hazard Ratio ◽  
Systemic Inflammatory Response ◽  
First Line ◽  
Lymphocyte Ratio ◽  
Pre Treatment ◽  
The Impact ◽  
Line Chemotherapy

88 Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings, such as gender, age, body mass index (BMI), tumor status (unresectable vs. recurrent, intestinal vs. diffuse), number of metastatic sites, serum levels of albumin (Alb) and C-reactive protein (CRP), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR), were assessed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses. Results: Median OS and PFS were 390 days and 175 days for SI arm, and 363 days and 140 days for SP arm, respectively. Multivariate analysis identified the CRP level of 0.5 mg/dl or above (hazard ratio 1.96, 95% confidence interval 1.08 to 3.55, P=0.026) as a significant prognosticator for poor OS, and age of 60 years or greater (hazard ratio 1.92, 95% confidence interval 1.06–3.47, P=0.032) for shorter PFS. Conclusions: Pre-treatment CRP level was a most potent prognosticator for OS, reflecting the impact of systemic inflammatory response on survival, in AGC patients receiving first-line chemotherapy.

scholarly journals Seal or Varnish? A randomised controlled trial to determine the relative cost and effectiveness of pit and fissure sealant and fluoride varnish in preventing dental decay

2017 ◽  
Vol 21 (21) ◽  
pp. 1-256 ◽  
Author(s):  
Ivor Gordon Chestnutt ◽  
Simon Hutchings ◽  
Rebecca Playle ◽  
Sarah Morgan-Trimmer ◽  
Deborah Fitzsimmons ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Dental Caries ◽  
Budget Impact ◽  
Clinical Effectiveness ◽  
Health Technology ◽  
Fluoride Varnish ◽  
Relative Cost ◽  
Fissure Sealant ◽  
Randomised Controlled ◽  
To Receive

Background Fissure sealant (FS) and fluoride varnish (FV) have been shown to be effective in preventing dental caries when tested against a no-treatment control. However, the relative clinical effectiveness and cost-effectiveness of these interventions is unknown. Objective To compare the clinical effectiveness and cost-effectiveness of FS and FV in preventing dental caries in first permanent molars (FPMs) in 6- and 7-year-olds and to determine their acceptability. Design A randomised controlled allocation-blinded clinical trial with two parallel arms. Setting A targeted population programme using mobile dental clinics (MDCs) in schools located in areas of high social and economic deprivation in South Wales. Participants In total, 1016 children were randomised, but one parent subsequently withdrew permission and so the analysis was based on 1015 children. The randomisation of participants was stratified by school and balanced for sex and primary dentition baseline caries levels using minimisation in a 1 : 1 ratio for treatments. A random component was added to the minimisation algorithm, such that it was not completely deterministic. Of the participants, 514 were randomised to receive FS and 502 were randomised to receive FV. Interventions Resin-based FS was applied to caries-free FPMs and maintained at 6-monthly intervals. FV was applied at baseline and at 6-month intervals over the course of 3 years. Main outcome measures The proportion of children developing caries into dentine (decayed, missing, filled teeth in permanent dentition, i.e. D4–6MFT) on any one of up to four treated FPMs after 36 months. The assessors were blinded to treatment allocation; however, the presence or absence of FS at assessment would obviously indicate the probable treatment received. Economic measures established the costs and budget impact of FS and FV and the relative cost-effectiveness of these technologies. Qualitative interviews determined the acceptability of the interventions. Results At 36 months, 835 (82%) children remained in the trial: 417 in the FS arm and 418 in the FV arm. The proportion of children who developed caries into dentine on a least one FPM was lower in the FV arm (73; 17.5%) than in the FS arm (82, 19.6%) [odds ratio (OR) 0.84, 95% confidence interval (CI) 0.59 to 1.21; p = 0.35] but the difference was not statistically significant. The results were similar when the numbers of newly decayed teeth (OR 0.86, 95% CI 0.60 to 1.22) and tooth surfaces (OR 0.85, 95% CI 0.59 to 1.21) were examined. Trial fidelity was high: 95% of participants received five or six of the six scheduled treatments. Between 74% and 93% of sealants (upper and lower teeth) were intact at 36 months. The costs of the two technologies showed a small but statistically significant difference; the mean cost to the NHS (including intervention costs) per child was £500 for FS, compared with £432 for FV, a difference of £68.13 (95% CI £5.63 to £130.63; p = 0.033) in favour of FV. The budget impact analysis suggests that there is a cost saving of £68.13 (95% CI £5.63 to £130.63; p = 0.033) per child treated if using FV compared with the application of FS over this time period. An acceptability score completed by the children immediately after treatment and subsequent interviews demonstrated that both interventions were acceptable to the children. No adverse effects were reported. Limitations There are no important limitations to this study. Conclusions In a community oral health programme utilising MDCs and targeted at children with high caries risk, the twice-yearly application of FV resulted in caries prevention that is not significantly different from that obtained by applying and maintaining FSs after 36 months. FV proved less expensive. Future work The clinical effectiveness and cost-effectiveness of FS and FV following the cessation of active intervention merits investigation. Trial registration EudraCT number 2010-023476-23, Current Controlled Trials ISRCTN17029222 and UKCRN reference 9273. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 21. See the NIHR Journals Library website for further project information.

Treatment Disparities in Hispanic Rectal Cancer Patients: A SEER Database Study

2006 ◽  
Vol 72 (10) ◽  
pp. 906-908 ◽  
Author(s):  
Steve R. Martinez ◽  
Steven L. Chen ◽  
Anton J. Bilchik
Keyword(s):  
Rectal Cancer ◽  
Confidence Interval ◽  
Neoadjuvant Therapy ◽  
Proportional Hazards Model ◽  
Hazard Ratio ◽  
Cox Proportional Hazards Model ◽  
Seer Database ◽  
Treatment Disparities ◽  
The Impact ◽  
To Receive

Although Hispanics demonstrate a low overall incidence of rectal cancer, mortality rates have not decreased relative to non-Hispanic whites. To determine if this was in part due to racial disparities in care, we compared rates of neoadjuvant therapy and sphincter-preserving surgery between Hispanics and non-Hispanic whites diagnosed with rectal cancer using the Surveillance, Epidemiology, and End Results (SEER) database. The study population was comprised of 2,573 Hispanics (55.4% male) and 28,395 non-Hispanic whites (56.6% male). Rates of neoadjuvant radiation were 13.5 per cent for Hispanics compared with 10.4 per cent for non-Hispanic whites (P < 0.001). In a Cox proportional hazards model adjusting for nodal status, tumor size, and T stage, non-Hispanic whites were significantly less likely to have received neoadjuvant therapy (hazard ratio, 0.72; P < 0.001; 95% confidence interval 0.63–0.83). Rates of sphincter preservation were 67 per cent for Hispanics and 70 per cent for non-Hispanic whites (P = 0.003). Non-Hispanic whites were significantly more likely to have received a sphincter-preserving operation than Hispanics (hazard ratio, 1.076; P = 0.019; 95% confidence interval 1.02–1.27). We conclude that Hispanics are significantly more likely to receive neoadjuvant therapy but are less likely to receive sphincter-sparing operations for rectal cancer compared with non-Hispanic whites. Further studies are required to assess the impact of these treatment disparities on patient outcome.

TP53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with anti-angiogenic or standard chemotherapy regimens.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16571-e16571
Author(s):  
Nicholas William Fischer ◽  
Francesco Graziano ◽  
Irene Bagaloni ◽  
Maria Di Bartolomeo ◽  
Sara Lonardi ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Tp53 Mutation ◽  
Current Data ◽  
Hazard Ratio ◽  
Control Group ◽  
First Line ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Angiogenic Potential ◽  
Therapy Strategies

e16571 Background: Current data support the angiogenic potential of cancer cells with mutant p53 and VEGF-A up-regulation in solid tumors. These findings have renewed interest in the p53 role as a predictive/prognostic factor in cancer therapy. We investigated TP53 mutations in gastric adenocarcinoma (GA) samples of metastatic patients (pts) who underwent anti-angiogenic Paclitaxel-Ramucirumab (PR) therapy. The analysis was also performed in a control group of pts who received first-line chemotherapy (CT) with platinum derivates and fluoropyrimidines. Methods: TP53 mutations were identified by next-generation sequencing in 110 GA primary tumors of two retrospective metastatic series including 48 pts who were treated with second-line PR and 62 pts who received first-line CT with Cisplatin or Oxaliplatin plus 5-Fluorouracil or Capecitabine. Detected TP53 mutations were classified for TP53 mutant-specific residual transcriptional activity scores ( TP53 RTAS) (Fischer NW et al JCI Insight 2018). TP53 RTAS results were used for stratifying pts in survival analyses. Primary end-point was overall survival (OS). Results: In the PR group, TP53 mutations were detected in 29 out of 48 tumor samples (60.4%) with 10 having TP53 RTAS 0%-to-<1%. In the CT group, TP53 mutations were found in 40 out of 62 tumor samples (64.5%) with 11 having TP53 RTAS 0%-to-<1%. In the PR group, the 10 cases with a TP53 mutation causing no residual or minimal activity ( TP53 RTAS 0%-to-<1%) showed better OS in comparison with pts in the remaining groups (wild-type and TP53 RTAS > 1%). This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval 0.17-0.85, p = 0.02). An opposite effect was seen in the CT group with the worst OS in carriers of TP53 RTAS 0%-to-<1% mutations (Hazard Ratio = 2.64, 95% confidence interval 1.17-5.95, p = 0.02). Notably, in the whole group of 110 pts, TP53 mutations (any type) occurred more frequently in the intestinal-type GA group (p = 0.02). Conclusions: Additional studies are warranted to explore the favorable role of TP53 mutations in cancer pts undergoing anti-angiogenic therapies. TP53 mutations frequently occur in GA and these findings would lead to novel tailored therapy strategies in this lethal disease.

scholarly journals Assessment of Clinical and Economic Effectiveness of Alectinib for Patients with ALK+ Non-Small Cell Lung Cancer without Previous Experience of Targeted Therapy

2019 ◽  
pp. 87-100
Author(s):  
Sergey Vladimirovich Nedogoda ◽  
Alla Sergeevna Salasyuk ◽  
Irina Nikolaevna Barykina ◽  
Victoria Olegovna Smirnova ◽  
Ekaterina Andreevna Popova
Keyword(s):  
Cost Effectiveness ◽  
Budget Impact ◽  
Clinical Effectiveness ◽  
Small Cell ◽  
Cost Effectiveness Ratio ◽  
Small Cell Lung ◽  
First Line ◽  
System Perspective ◽  
Healthcare System Perspective ◽  
One Year

Aim: to assess economic consequences of alectinib compared with the recommended therapy schemes for patients with non-small cell lung cancer (NSCLC) with tumor expression of anaplastic lymphoma kinase (ALK+) without previous experience of targeted therapy from the Russian healthcare system perspective. Material and methods. Markov model was developed in Microsoft Excel 2010 software for cost calculation. 5-year costs of alectinib, crizotinib and ceritinib were calculated, taking into account the differences in clinical effectiveness and safety of the compared drugs. Data about clinical effectiveness and safety were derived from the network meta-analysis Steenrod A. et al, 2018, where alectinib showed superior effectiveness in the first line of therapy for ALK+ NSCLC vs crizotinib and ceritinib: relative risk (RR) of progression-free survival (PFS) was 0,50 (95% confidence interval 0,36–0,70) and 0,41 (0,25–0,67) respectively. Safety of alectinib in the first line therapy was superior to the safety of ceritinib – RR of severe adverse events (SAE)3–4 grade 0,36 (95% CI 0,17–0,79), – and was comparable with safety of chemotherapy and crizotinib – RR of SAE 3–4 grade 0,81 (95% CI 0,44–1,52) and 0,65 (95% CI 0,51–1,04) respectively. Cost effectiveness analyses and budget impact analysis were conducted from the Russian healthcare system perspective. Results. Cost of one year course of alectinib was 3 431 970 rubles, which was comparable with crizotinib (3 435 405 rub.) and 55% higher than the one-year cost of ceritinib. Cost-effectiveness ratio was lower for alectinib compared with crizotinib, incremental cost-effectiveness ratio (ICER) for alectinib vs crizotinib was 2 735 900 rub., which was 66% lower than ICER for ceritinib vs crizotinib. Given the number of patients eligible for alectinib, it’s impact on State Guarantees Program of Free Medical Care is not much. Sensitivity analysis showed that the results of budget impact assessment are stable. Conclusion. Alectinib is a preferred option for patients with ALK+ NSCLC from economic point of view. It doesn’t have a significant impact on the budget within the State Guarantees Program of Free Medical Care, and also has higher effectiveness compared with crizotinib and ceritinib and better safety when compared with ceritinib.

scholarly journals Pembrolizumab (Keytruda)

2021 ◽  
Vol 1 (9) ◽  
Author(s):  
Reimbursement Team
Keyword(s):  
Colorectal Cancer ◽  
Cost Effectiveness ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Drug Class ◽  
Clinical Effectiveness ◽  
Line Treatment ◽  
First Line ◽  
Clinician Perspectives ◽  
First Line Treatment

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses pembrolizumab (Keytruda) 200 mg administered intravenously Indication: As monotherapy, for the first-line treatment of adults with metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer

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