Converging or Crossing Curves: Untie the Gordian Knot or Cut it? Appropriate Statistics for Non-Proportional Hazards in Decitabine DACO-016 Study (AML)

Introduction: Among patients with acute myeloid leukemia (AML), the DACO-016 randomized study showed reduction in mortality for decitabine [Dacogen® (DAC), Eisai Inc., Woodcliff Lake, NJ, USA] compared with treatment choice (TC): at primary analysis the hazard ratio (HR) was 0.85 (95% confidence interval 0.69-1.04; stratified log-rank P=0.108). With two interim analyses, two-sided alpha was adjusted to 0.0462. With 1-year additional follow-up the HR reached 0.82 (nominal P=0.0373). These data resulted in approval of DAC in the European Union, though not in the United States. Though pre-specified, the log-rank test could be considered not optimal to assess the observed survival difference because of the non-proportional hazard nature of the survival curves. Methods: We applied the Wilcoxon test as a sensitivity analysis. Patients were randomized to DAC (N=242) or TC (N=243). One-hundred and eight (44.4%) patients in the TC arm and 91 (37.6%) patients in the DAC arm selectively crossed over to subsequent disease modifying therapies at progression, which might impact the survival beyond the median with resultant converging curves (and disproportional hazards). Results: The stratified Wilcoxon test showed a significant improvement in median (CI 95%) overall survival with DAC [7.7 (6.2; 9.2) months] versus TC [5.0 (4.3; 6.3) months; P=0.0458]. Conclusion: Wilcoxon test indicated significant increase in survival for DAC versus TC compared to log-rank test. Funding: Janssen-Cilag GmbH

Comparative effectiveness of depot and oral second generation antipsychotic drugs in schizophrenia: A nationwide study in Hungary.

We conducted a nationwide, full-population based investigation to evaluate the comparative effectiveness of all marketed second generation antipsychotic drugs (SGA) prescribed for outpatients with the diagnosis of schizophrenia in Hungary. Using the national central register, our observational follow-up study included all patients with schizophrenia or related disorder between 01/01/2006 and 30/06/2008. The study cohort comprised 9567 patients who started new SGA during the inclusion period (01/07/2007-30/06/2008). All-cause medication discontinuation of 8 SGAs (1 depot and 7 oral formulations) marketed during the inclusion period, and the time to all-cause discontinuation were the main outcomes. Statistical models included the Kaplan-Meier and the Cox proportional hazards models with propensity score adjustment. Patients treated with a depot formulation risperidone had the longest time to discontinuation with a median of 215 days (95%CI:181-242 days), which was statistically significantly different compared to patients treated with the rest of the medications: olanzapine (136 days, 95%CI:121-153 days), aripiprazole (102 days, 95%CI:81-126 days), ziprasidone (93 days, 95%CI:82-119 days), quetiapine (89 days, 95%CI:81-100 days), clozapine (76 days, 95%CI:54-92 days), amisulpride (73 days, 95%CI:62-85 days), and risperidone (55 days, 95%CI: 41-63 days). Our results in Hungary are partly similar to those of a recent register-based study in Finland with patients who were discharged from their first hospitalization for schizophrenia (Tiihonen et al., 2006, 2011); namely the median times to all-cause medication discontinuation were <120 days for the majority of the oral SGA. In terms of medication differences, our data support the superior effectiveness of the depot formulation regarding all-cause discontinuation, followed by olanzapine at the efficacy rank order

Adjusted Comparison of Outcomes between Patients from CARTITUDE-1 versus Multiple Myeloma Patients with Prior Exposure to PI, Imid and Anti-CD-38 from a German Registry

Ciltacabtagene autoleucel (cilta-cel) is a Chimeric antigen receptor T-cell therapy with the potential for long-term disease control in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM). As cilta-cel was assessed in the single-arm CARTITUDE-1 clinical trial, we used an external cohort of patients from the Therapie Monitor registry fulfilling the CARTITUDE-1 inclusion criteria to evaluate the effectiveness of cilta-cel for overall survival (OS) and time to next treatment (TTNT) vs. real-world clinical practice. Individual patient data allowed us to adjust the comparisons between both cohorts, using the inverse probability of treatment weighting (IPW; average treatment effect in the treated population (ATT) and overlap population (ATO) weights) and multivariable Cox proportional hazards regression. Outcomes were compared in intention-to-treat (HR, IPW-ATT: TTNT: 0.13 (95% CI: 0.07, 0.24); OS: 0.14 (95% CI: 0.07, 0.25); IPW-ATO: TTNT: 0.24 (95% CI: 0.12, 0.49); OS: 0.26 (95% CI: 0.13, 0.54)) and modified intention-to-treat (HR, IPW-ATT: TTNT: 0.24 (95% CI: 0.09, 0.67); OS: 0.26 (95% CI: 0.08, 0.84); IPW-ATO: TTNT: 0.26 (95% CI: 0.11, 0.59); OS: 0.31 (95% CI: 0.12, 0.79)) populations. All the comparisons were statistically significant in favor of cilta-cel. These results highlight cilta-cel’s potential as a novel, effective treatment to address unmet needs in patients with RRMM

Comparative Efficacy of Ciltacabtagene Autoleucel Versus Standard-of-Care Treatments for Patients with Previously Treated Relapsed or Refractory Multiple Myeloma: A Matching-Adjusted Indirect Comparison

Introduction: Matching adjusted indirect comparisons (MAICs) were performed to compare the efficacy of cilta-cel versus elotuzumab&nbsp;+&nbsp;pomalidomide&nbsp;+&nbsp;dexamethasone (EloPd), isatuximab&nbsp;+&nbsp;carfilzomib&nbsp;+&nbsp;dexamethasone (IsaKd), isatuximab&nbsp;+&nbsp;pomalidomide&nbsp;+&nbsp;dexamethasone (IsaPd), and selinexor&nbsp;+&nbsp;bortezomib&nbsp;+&nbsp;dexamethasone (SVd) in patients with&nbsp;relapsed or refractory multiple myeloma (RRMM) who have received at least one prior therapy and are lenalidomide-refractory. Methods: Unanchored MAICs were performed using individual patient-level data (IPD) for all apheresed patients randomized to the cilta-cel arm of CARTITUDE-4 (n =&nbsp;208) and published arm-level data for EloPd from ELOQUENT-3 (n&nbsp;=&nbsp;60), IsaKd from IKEMA (lenalidomide-refractory subgroup, n&nbsp;=&nbsp;57), IsaPd from ICARIA-MM (n&nbsp;=&nbsp;154), and SVd from BOSTON (lenalidomide-refractory subgroup, n&nbsp;=&nbsp;53). Eligibility criteria from each comparator trial were applied to the cilta-cel arm IPD, and further imbalances in patient characteristics were adjusted by weighting the cilta-cel patient data to match the reported baseline characteristics of the comparator trials. Comparative efficacy was estimated for overall response rate, very good partial response or better (≥&nbsp;VGPR) rate, complete response or better (≥&nbsp;CR) rate, progression-free survival (PFS), and overall survival (OS). Results: After adjustment, cilta-cel patients were significantly more likely to achieve an overall response versus EloPd, IsaPd, and SVd, and were significantly more likely to achieve&nbsp;≥&nbsp;VGPR and&nbsp;≥&nbsp;CR versus all comparators. Cilta-cel patients also had significant reductions in the risk of disease progression or death (PFS) versus all comparators: 64% versus EloPd, 49% versus IsaKd, 69% versus IsaPd, and 62% versus SVd. Similarly, cilta-cel patients had significant improvements in OS for all feasible comparisons: 52% versus EloPd, 58% versus IsaPd, and 60% versus SVd. Conclusion: Cilta-cel patients demonstrated clinically meaningful benefits over EloPd, IsaKd, IsaPd, and SVd for response and survival outcomes, highlighting its superiority over alternative treatment options for patients with RRMM who have received at least one prior therapy and are refractory to lenalidomide

Adjusted comparison of outcomes between patients from CARTITUDE-1 <i>versus</i> multiple myeloma patients with prior exposure to proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibody from the prospective, multinational LocoMMotion study of real-world clinical practice

Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy studied in patients with multiple myeloma exposed to three classes of treatment in the single-arm CARTITUDE-1 study. To assess the effectiveness of cilta-cel compared to real-world clinical practice (RWCP), we performed adjusted comparisons using individual patients’ data from CARTITUDE-1 and LocoMMotion, a prospective, multinational study of patients with multiple myeloma triple-class exposed of treatment. Comparisons were performed using inverse probability weighting. In CARTITUDE-1, 113 patients were enrolled, and 97 patients were infused with cilta-cel. In LocoMMotion, 248 patients were enrolled, and 170 patients were included in the comparisons versus infused patients. Ninety-two unique regimens were used in LocoMMotion, most frequently carfilzomib-dexamethasone (13.7%), pomalidomide-cyclophosphamide-dexamethasone (13.3%) and pomalidomidedexamethasone (11.3%). Adjusted comparisons showed that patients treated with cilta-cel were 3.12-fold more likely to respond to treatment than those managed by RWCP (response rate, 3.12, 95% confidence interval [95% CI]: 2.24-4.00), had their risk of progression or death reduced to by 85% (progression-free survival hazard ratio=0.15, 95% CI: 0.08-0.29), and a risk of death lowered by 80% (overall survival hazard ratio HR=0.20, 95% CI: 0.09-0.41). The incremental improvement in healthrelated quality of life from baseline for cilta-cel versus RWCP at week 52, as measured by EORTC QLQ-C30 Global Health Status, was 13.4 (95% CI: 3.5-23.6) and increased to 30.8 (95% CI: 21.8-39.8) when including death as additional information regarding patients’ health status. Patients treated with cilta-cel experienced more adverse events than those managed with RWCP (any grade: 100% vs. 83.5%). The results from this study demonstrate improved efficacy outcomes of cilta-cel versus RWCP and highlight its potential as a novel and effective treatment option for patients with multiple myeloma triple-class exposed of antimyeloma treatment. CARTITUDE-1 is registered with clinicaltrials gov. Identifier: NCT03548207. LocoMMotion is registered with clinicaltrials gov. Identifier: NCT04035226

Validiteit van IZIKA/IZIIK instrument voor doelgroep kinderen en jongeren met een handicap

Voorliggend rapport sluit aan bij breder onderzoek rond de implementatie van het IZIKA en IZIIK-instrument in het kader van de Intersectorale Toegangspoort voor Jeugdhulp. Het focust meerbepaald op de inschatting van zorgintensiteit voor kinderen en jongeren met een verstandelijke, motorische, zintuiglijke en/of meervoudige handicap. Het project zal de invulling en determinerende elementen van het begrip zorgintensiteit uit literatuur te vergelijken met de invulling van zorgniveaus/-items in IZIKA/IZIIK en voor elk van de geformuleerde subdoelgroepen te deze vergelijking te toetsen aan de mening van praktijkdeskundigen (professionele deskundigen m.b.t. de respectievelijke subdoelgroepen ). Verder tracht het onderzoek bij bestaande geanonimiseerde dossiers het geïndiceerde IZIKA/IZIIK – zorgniveau te correleren met een gemiddeld klinisch ordinaal oordeel. Het project geeft aanbevelingen bij gebruik van het instrument, en aan hulpverleners/verwijzers de aansluiting met andere mogelijke zorgzwaarte-instrumenten te duiden.status: publishe

De Oer-Faust : Overdruk van het afschrift van Fräulein von Göchhausen / Goethe. Met een vertaling door Joris Diels en een inleiding en een voordracht van Carl Niessen

DE OER-FAUST : OVERDRUK VAN HET AFSCHRIFT VAN FRÄULEIN VON GÖCHHAUSEN / GOETHE. MET EEN VERTALING DOOR JORIS DIELS EN EEN INLEIDING EN EEN VOORDRACHT VAN CARL NIESSEN De Oer-Faust : Overdruk van het afschrift van Fräulein von Göchhausen / Goethe. Met een vertaling door Joris Diels en een inleiding en een voordracht van Carl Niessen (1) Einband (1) Kapitel (10) Titelblatt (12) Kapitel (14) Bildtafel: Faust en Greetje / Greetje (15) Voorwoord van den uitgever (16) Bildtafel: Faust en Wagner (18) Bildtafel: Tooverteekens ... (19) Bildtafel: Faust en Wagner (doppelt) (20) Bildtafel: Tooverteekens ... (doppelt) (21) Verantwoording van den vertaler (22) Bezetting (23) Inkleeding en Tooneel voor de Vlaamsche opvoering van Goethe's Oer-Faust (Carl Niessen) (24) Bildtafel: Figurinen Siebel en Frosch (26) Bildtafel: Martha's kamer (27) Bildtafel: Figurinen Siebel en Frosch (doppelt) (28) Bildtafel: Martha's kamer (doppelt) (29) Inkleeding en Tooneel voor de Vlaamsche opvoering van Goethe's Oer-Faust (Carl Niessen) (30) Bildtafel: Mephisto en de Student / Mephisto en Martha (36) Inkleeding en Tooneel voor de Vlaamsche opvoering van Goethe's Oer-Faust (Carl Niessen) (37) Der Urfaust / De Oer-Faust (41) Goethe's Oer-Faust (Carl Niessen) (178) Bildtafel: In Auerbach's kelder (200) Goethe's Oer-Faust (Carl Niessen) (201) Bildtafel: Figurinen Faust en Greetje (206) Bildtafel: Decorontwerpen voor Tuin- en Spinnewielmonologen (207) Goethe's Oer-Faust (Carl Niessen) (208) Bildtafel: Greetje's gebed (212) Bildtafel: Figurinen Valentijn en Liesje (213) Goethe's Oer-Faust (Carl Niessen) (214) Bildtafel: Kerker (216) Goethe's Oer-Faust (Carl Niessen) (217) Literatuur (220) Inhoudsopgave, Drukfouten (222