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MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. National Institutes of Health and National Cancer Institute.

In phase 2 and 3 randomized, controlled trials, baloxavir — an inhibitor of influenza cap-dependent endonuclease — showed evidence of clinical symptom relief and antiviral activity against influenza. However, influenza-resistant variants appeared to develop with treatment.

In a randomized, double-blind trial that treated household contacts of patients with influenza with a single dose of baloxavir or placebo, participants taking baloxavir had a lower risk of influenza (1.9%) than placebo controls (13.6%). Adverse events were similar in the two groups.

In this randomized trial conducted over the 2019–2024 influenza seasons, baloxavir resulted in a significantly lower incidence of transmission of influenza virus from patients to household contacts than placebo.

Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200–800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, “high” vs “low”), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80–125%) in the analysis population. This study is registered with ClinicalTrials.gov\\, number NCT01713777. Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98–103, Cmax 90% CI 99–105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

In this randomized trial of three common treatments for childhood absence epilepsy, ethosuximide and valproic acid were more effective than lamotrigine, and adverse effects on attention were less frequent with ethosuximide than with valproic acid. These findings suggest that ethosuximide has the best efficacy and safety profile. The findings of this randomized trial of three common treatments for childhood absence epilepsy suggest that ethosuximide has the best efficacy and safety profile. Childhood absence epilepsy accounts for 10 to 17% of all cases of childhood-onset epilepsy, making it the most common form of pediatric epilepsy. 1 , 2 The syndrome is characterized by daily frequent but brief staring spells, typically beginning at 4 to 8 years of age, in an otherwise apparently healthy child. 3 The classic electroencephalogram (EEG) shows generalized spike-wave bursts (of 3 Hz) with normal background activity. 3 , 4 Often misperceived as a benign form of epilepsy, childhood absence epilepsy is associated with variable remission rates; affected children have cognitive deficits and long-term psychosocial difficulties. 5 – 7 Three medications are commonly used as initial . . .

Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

In a phase 3 trial, vorasidenib, an oral brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), resulted in improved progression-free survival (primary endpoint) and time to next intervention (key secondary endpoint) at second interim analysis, resulting in study unblinding. We report 6 months of additional double-blind data, from second interim analysis (Sept 6, 2022) to unblinding (March 7, 2023), and the effect of vorasidenib on volumetric tumour growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control. INDIGO was a randomised, double-blind, placebo-controlled, phase 3 trial done in 92 hospitals in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the UK, and the USA. Patients aged 12 years or older with residual or recurrent grade 2 IDH1/2-mutant diffuse glioma, a Karnofsky performance-status score of 80 or higher, at least one previous surgery, and no other previous anticancer treatment were eligible. Patients were randomly assigned (1:1; stratified according to locally determined chromosome 1p/19q codeletion status and baseline tumour size) to oral vorasidenib (40 mg) or placebo once a day in continuous 28-day cycles until disease progression or unacceptable toxicity. Progression-free survival per masked independent review committee was the primary endpoint, and time to next intervention was the key secondary endpoint. Prespecified secondary endpoints included tumour growth rate (6-monthly change in tumour volume) and HRQOL (Functional Assessment of Cancer Therapy–Brain [FACT-Br]). Prespecified exploratory endpoints included neurocognitive function (cognitive performance instruments) and seizure activity (self-reported). The full analysis set was used for all efficacy analyses and included all randomly assigned patients, and the safety analysis set was used for all safety analyses and included all patients who received one or more doses of vorasidenib or placebo. The trial is registered with ClinicalTrials.gov, NCT04164901. Recruitment is complete and the trial is ongoing. Between Jan 9, 2020, and Feb 22, 2022, 331 patients were enrolled and randomly assigned to vorasidenib (n=168) or placebo (n=163). 187 (56%) patients were male, 144 (44%) were female, and 257 (78%) were White. Median follow-up was 20·1 months (IQR 15·9 to 23·8). With an additional 6 months of follow-up, median progression-free survival (not reached [95% CI 22·1 to not estimated] vs 11·4 months [95% CI 11·1 to 13·9]; hazard ratio [HR] 0·35 [95% CI 0·25 to 0·49]) and time to next intervention (not estimated [not estimated to not estimated] vs 20·1 months [17·5 to 27·1]; HR 0·25 [0·16 to 0·40]) remained substantially improved with vorasidenib versus placebo. Tumour growth rate was –1·3% (95% CI –3·2 to 0·7) with vorasidenib and 14·4% (95% CI 12·0 to 16·8) with placebo (difference 15·9% [95% CI 12·6 to 19·3]). Mean FACT-Br total scores were similar between the vorasidenib and placebo groups (158·2 [SD 26·4] and 158·8 [23·3]) at baseline and remained high (154·2 [29·8] and 153·2 [29·4]) by the end of treatment. There was no difference between vorasidenib or placebo in neurocognitive functions of verbal learning, executive function, attention, working memory, and psychomotor function from baseline through to end of treatment. The vorasidenib group had lower rates of seizures than the placebo group (18·2 seizures per person-year [95% CI 8·4 to 39·5] vs 51·2 seizures per person-year [22·9 to 114·8]). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) in the vorasidenib and placebo groups, respectively, were increased alanine aminotransferase (17 [10%] and two [1%]), increased aspartate aminotransferase (eight [5%] and none), seizures (seven [4%] and five [3%]), and increased γ-glutamyltransferase (five [3%] and two [1%]). Serious TEAEs occurred in 20 (12%) patients in the vorasidenib group and ten (6%) in the placebo group; the most common were seizures. There were no treatment-related deaths. Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition. Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma. These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy. Servier.

Background Seasonal influenza virus leads to more than half a million deaths each year worldwide. Due to its capacity to evolve, it is considered the most likely pathogen to cause a future pandemic. Antiviral treatment options are currently limited, with the most widely used drugs being neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir marboxil. In adult hospitalized patients, due to the lack of placebo-controlled trials, current available evidence on antiviral treatment benefits is essentially based on observational studies. A placebo-controlled clinical trial is needed to fill this knowledge gap. Methods This is an investigator-initiated, randomized, triple-blind, placebo-controlled, superiority, multi-center trial to assess the clinical efficacy of single-dose baloxavir in decreasing time to clinical improvement in adult immunocompetent patients hospitalized with influenza. Patients ( n  = 484) with confirmed, severe infection (NEWS2 score ≥ 4) will be recruited over three influenza seasons in four large Swiss hospitals. Primary outcome: time to clinical improvement (in hours), calculated from treatment administration until NEWS2 score ≤ 2 maintained for 24 h or until hospital discharge, whichever comes first. The primary outcome is calculated in all patients independently of the duration of symptoms at treatment administration, as well as in participants treated early (<72 h) post onset of symptoms. The main secondary outcomes are the risk of serious influenza complications, length of hospitalization, and difference in viral load at D3 post-treatment administration. Discussion This trial’s results, whether positive or negative, will impact clinical guidance. If baloxavir’s clinical benefit is demonstrated, a single-dose pill would be the easiest implementable treatment option in case of large seasonal outbreaks or a new influenza pandemic. If a clear treatment benefit is not shown, antiviral treatment administration in the hospitalized patient population could be reconsidered to prevent unnecessary medication, lower the risk of resistance development linked to treatment overuse, and ultimately save unnecessary treatment-related expenses. Trial registration ClinicalTrials.gov NCT06653569. Registered on October 22, 2024, https://clinicaltrials.gov/study/NCT06653569?term=NCT06653569&rank=1 .

Background Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). Methods This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan–Meier survival curves were compared by Cox regression. Results Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose ( n  = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan–Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 ( P =  0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 ( P =  0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. Conclusions In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. Trial registration The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .