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 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

scholarly journals Cetuximab for the first-line treatment of metastatic colorectal cancer

2010 ◽  
Vol 14 (Suppl 1) ◽  
pp. 1-8
Author(s):  
C Meads ◽  
J Round ◽  
S Tubeuf ◽  
D Moore ◽  
M Pennant ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cost Effectiveness ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Clinical Effectiveness ◽  
Economic Evaluations ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
First Line Treatment

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer (mCRC), in accordance with the licensed indication, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The ERG project ran between 22 January 2008 and 4 November 2008. The clinical evidence came from two unpublished randomised controlled trials (RCTs) of cetuximab plus chemotherapy versus chemotherapy alone in the first-line treatment of mCRC. A third RCT submitted later compared cetuximab with irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) and cetuximab with oxaliplatin in combination with 5-FU and FA in patients with mCRC with liver metastases only. No published economic evaluations of cetuximab for first-line chemotherapy in mCRC were identified in the submission. A de novo model examined the cost-effectiveness of cetuximab in patients with mCRC that was epidermal growth factor receptor positive, k-ras wild type and with liver metastases. The main source of clinical effectiveness evidence came from the first two RCTs which provided follow up information for 1–2 years. Secondary information was used to estimate survival for a further 22 years. The model focused on the patients for whom the treatment had been licensed. This limited the applicability of the model to the NHS setting in which patients would be a mixture of k-ras wild type and mutations and also a mixture of patients with liver metastases and other metastases. The difference in progress-free survival for the two trials was between 0.5 to 1.2 months over a 7–10 month period. Eight months’ treatment with cetuximab, given as an initial loading dose and then weekly until progression, would cost around £22,932 for an average man and £18,427 for an average woman. It is uncertain whether this constitutes good value for money. The guidance issued by NICE on 25 September 2008 stated that cetuximab was not recommended for the first-line treatment of mCRC and people currently receiving cetuximab for the first-line treatment of mCRC should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

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