Dashboard-Driven Accelerated Infliximab Induction Dosing Increases Infliximab Durability and Reduces Immunogenicity

Background and Aims Accelerated infliximab (IFX) induction is often based on clinical parameters as opposed to pharmacokinetics (PK). We aimed to investigate the impact of dashboard-guided optimized induction dosing on IFX durability and immunogenicity in a real-world inflammatory bowel disease (IBD) setting. Methods Pediatric and adult IBD patients were enrolled in a prospective single arm intervention trial. Cumulative data from each infusion (INF), weight, albumin, C-reactive protein, IFX dose, IFX trough level, and antidrug antibody presence were used to inform subsequent INF dosing. Forecasts driven by adaptive Bayesian modeling were generated to maintain trough levels for the third (INF3) and fourth (INF4) infusions of 17 μg/mL and 10 μg/mL, respectively. The primary outcome was proportion of patients prescribed accelerated dosing (AD) intervals by INF3 (<22 days) or INF4 (<49 days). Secondary outcomes included week 52 clinical and PK outcomes. Multivariate analyses and Kaplan-Meier curves compared outcomes based on adherence to dashboard forecasts. Results Of the 180 per-protocol population, AD was forecast for 41% (INF3) and 69% (INF4) of patients with median intervals of 17 (INF3) and 39 (INF4) days. Baseline age >18 years, albumin >3.5 g/L, and 10-mg/kg dose were independently associated with lower rates of AD by INF4. Nonadherence with the INF4 forecast (n = 39) was an independent predictor of antidrug antibody (P < .0001) and IFX discontinuation (P = .0006). A total of 119 of 123 patients on IFX at week 52 were in steroid-free remission. Conclusions The application of a PK dashboard during induction can optimize dosing early to improve IFX durability and immunogenicity.

Radiotherapy (WBRT) or Autologous Stem-Cell Transplantation (ASCT) for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Long-Term Results of the Intergroup Anocef-Goelams Randomized Phase II Precis Study

Introduction: We previously reported the results of the PRECIS trial with a median follow-up of 33 months. Both whole brain radiotherapy (WBRT) and autologous stem cell transplantation (ACST) were effective according to the predetermined threshold. However, more relapses occurred in the WBRT arm. The 2-year event-free survival (EFS) from consolidation (relapse or death defined as event) were 69% (95% CI, 57% to 83%) and 87% (95% CI, 77% to 98%) after WBRT and ASCT, respectively (p = 0.03). Overall survival (OS) was similar in both arms. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT. A longer follow-up is required to better assess the impact of the treatment on relapse, survival and late complications. We report here the results of the PRECIS trial with a median follow-up of 98.3 months [min= 4,1 - max= 131.1], focusing on the per protocol population from time of consolidation. Methods: Immunocompetent patients (18 to 60 years of age) with untreated primary CNS lymphoma (PCNSL) were randomly assigned upfront to receive WBRT (Arm A) or ASCT (Arm B) as consolidation treatment after an induction chemotherapy consisting of two cycles of R-MBVP (rituximab, methotrexate, VP16, BCNU, prednisone) followed by two cycles of R-AraC (rituximab, cytarabine). Intensive chemotherapy consisted of thiotepa (250 mg/m2/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/ fraction). Cognitive functions were prospectively assessed until disease progression and focused on global cognitive function, episodic verbal memory, attention and mental flexibility, and psychoaffective status. Results: 140 patients were randomized (Arm A: N = 70; Arm B: N = 70). Fifty-three and 44 patients completed WBRT and ASCT respectively (per protocol population), including 3 and 5 patients who were in progressive disease (PD) at time of WBRT and ASCT, respectively. 8-y EFS from time of consolidation in the per protocol population was 75.9% [63.3-91.0] and 39.9% [26.8-59.3] after ASCT and WBRT, respectively (p = 0.007) (fig 1a). The risk of relapse was significantly decreased after ASCT compared to WBRT (8-y relapse-free interval 94.1% [86.4-100] vs 47.6% [34.2-66.3], (p <0.001) (fig 1b). The 8-year overall survival from time of consolidation was similar in both arms, 63.4% [49.8 - 80.6] and 69.3% [56.7-84.8] in the WBRT and ASCT arms, respectively (fig1c). Among the 24 patients who relapsed after WBRT, 13 patients received subsequent salvage chemotherapy and consolidative ASCT, and seven of these patients were disease-free at last follow-up. Causes of deaths after WBRT (n = 17) were PD (n = 12), neurotoxicity (n = 3), second-line ASCT (n = 2). After ASCT, causes of deaths (n = 14) were treatment-related death (n = 5, including 2 occurring > 100 days post-ASCT, and 2 in patients in PD before ASCT), PD (n = 4), neurotoxicity following salvage WBRT (n = 1), second solid cancer (n = 3) and undetermined in one patient. In multivariate analysis, ECOG, disease status at the end of induction, and protein level in the CSF at diagnosis were independent prognostic factors for OS. Disease status at the end of induction and intraocular involvement at diagnosis were independent prognostic factors for EFS. Cognitive decline that could be fatal was only observed in patients who received WBRT. Imaging analysis of post consolidation leukoencephalopathy is ongoing. Conclusions: Consolidation with ASCT after HD-MTX based induction chemotherapy resulted in an excellent disease control but with a higher treatment-related mortality than WBRT. Severe Cognitive decline and late treatment-induced neurotoxic deaths were observed after WBRT. Intensity of the thiotepa-busulfan-cyclophosphamide regimen used before ASCT should be slightly reduced to improve the benefit/risk ratio of ASCT in first-line treatment of young patients with PCNSL. Figure 1 Figure 1. Disclosures Sylvain: Sanofi, Celegene, Roche, Abbvie, Sandoz, Janssen, Takeda: Consultancy. Damaj: takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Clinical Characteristics, Management, and Natural History of Chronic Inducible Urticaria in a Pediatric Cohort

<b><i>Background:</i></b> Some forms of chronic urticaria (CU) can be specifically attributed to a response to a definite trigger, referred to as chronic inducible urticaria (CIndU). We aimed to assess the demographics, clinical characteristics, comorbidities, natural history, and management of pediatric patients with CIndU. <b><i>Methods:</i></b> Over a 6-year period, children presenting to the allergy clinic at the Montreal Children’s Hospital (MCH) with CIndU were prospectively recruited. CU was defined as the presence of wheals and/or angioedema, occurring for at least 6 weeks. A standardized diagnostic test was used to establish the presence of a specific form of urticaria. Resolution was defined as the absence of hives for 1 year without treatment. <b><i>Results:</i></b> Sixty-four patients presented with CIndU, of which 51.6% were male, with a median age of 12.5 (interquartile range 7.3, 15.9) years. Cold CU and cholinergic CU were the most common subtypes (60.3 and 41.3%, respectively). Basophil counts were undetectable in 48.4% of the cases, and C-reactive protein levels were elevated in 7.8% of patients. Of all cases, 71.4% were controlled with second-generation antihistamines. The resolution rate was of 45.3% (95% confidence interval 33.1–57.5%), based on per-protocol population within the 6-year course of the study. Resolution was more likely in patients who presented with well-controlled urticaria control test scores and elevated CD63 counts and in those suffering from thyroid comorbidity. <b><i>Conclusion:</i></b> The natural history of CIndU resolution in pediatric patients was relatively low and was associated with elevated CD63 levels, as well as thyroid comorbidity.

FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial

Background Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes. Methods The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated. Results Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours. Conclusions FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. ClinicalTrials.gov identifier NCT00433927.

Ticagrelor monotherapy beyond 1 month versus standard dual antiplatelet therapy after drug-eluting coronary stenting: a pre-specified per-protocol analysis of the GLOBAL LEADERS trial

Background In the GLOBAL LEADERS trial, the intention-to-treat (ITT) effect of ticagrelor monotherapy after 1 month of dual antiplatelet therapy (DAPT) was not superior to that of 12-month DAPT followed by aspirin alone in the prevention of 2-year all-cause mortality or new Q-wave myocardial infarction (MI) after coronary stenting. Intention-to-treat analyses can be affected by incomplete protocol adherence. We present a pre-specified per-protocol analysis. Purpose To determine whether 1 month of ticagrelor plus aspirin followed by 23 months of ticagrelor monotherapy is superior to 12 months of DAPT followed by aspirin alone in the per-protocol population of the GLOBAL LEADERS (NCT01813435). Methods The GLOBAL LEADERS compared two antiplatelet strategies after drug-eluting stenting for stable coronary artery disease or acute coronary syndromes. Per-protocol population consisted of randomized patients fulfilling enrollment criteria and receiving protocol-mandated treatment. Adherence to the allocated antiplatelet therapy was evaluated at discharge, 30 days, and 3, 6, 12, 18, and 24 months, with non-adherence reasons categorized following a hierarchical approach. A protocol-deviation was defined in the case of high perceived bleeding/thrombotic risk, a medical decision without evident clinical reason, patients unwilling to take study drugs, prescription error, logistical issues, unclear reasons. Baseline characteristics, including (but not limited to) age, sex, diabetes, prior PCI, were used to construct time-varying inverse probabilities for not deviation from the protocol to reconstruct a study population with no protocol-deviations. Protocol deviators were artificially censored at the time at which they deviated. The primary endpoint was the composite of 2-year all-cause mortality or non-fatal new Q-wave MI. We used a weighted pooled logistic regression to estimate the per-protocol rate ratio (RR) of experimental vs. control treatment for the primary endpoint. Results Of the 15,968 randomized patients, 805 out of 7,980 (10.1%) in experimental group and 537 out of 7,988 (6.7%) in control group were classified as protocol deviators and artificially censored by month 12, not contributing events in the second year. The events for the adherence-adjusted analysis were 279 in experimental group and 325 in control group (25 and 24 less than in ITT analysis, respectively). The estimated adherence-adjusted RR was 0.87 (95% CI: 0.74–1.02; p=0.09), comparable to the ITT RR (0.87; 95% CI: 0.75–1.01; p=0.07). Conclusion At per-protocol analysis, ticagrelor monotherapy after 1 month of DAPT was not superior to conventional treatment, in line with the previously reported ITT effect. Similar per-protocol and ITT effects can be accounted for similar per-protocol and ITT populations, as a substantial proportion of patients were non-adherent due to clinically grounded reasons (anticipated in the protocol) and, accordingly, not considered as protocol deviators. Funding Acknowledgement Type of funding source: Other. Main funding source(s): GLOBAL LEADERS was sponsored by the European Clinical Research Institute, which received funding from Biosensors International, AstraZeneca, and the Medicines Company.

First results of Russian multicenter prospective clinical study VICTORY II: Vamloset® and Co-Vamloset effectiveness and safety in patients with stage 2 and 3 arterial hypertension

VICTORY II study objective. Evaluation of Vamloset and Co-Vamloset safety and effectiveness in reaching target blood pressure (BP) level in patients with stages 23 arterial hypertension (AH). Materials and methods. Russian multicenter prospective clinical study conducted in 8 clinical centers in6 cities in Russian Federation included 103 patients over 18 years of age with diagnosed essential hypertension of stages 23 (in accordance with 2013 European guidelines) who previously did not receive treatment (with office systolic BP sBP160 mm Hg and/or office diastolic BP dBP100 mmHg) or did not achieve target BP levels after receiving mono- or dual therapy. Office BP target levels comprised 139 mmHg for sBP and 89 mm Hg for dBP for patients without diabetes mellitus (DM), and 139 mm Hg for sBP and 84 mm Hg for dBP for patients with DM. All patients with stage 2 AH (group 1) were prescribed Vamloset (amlodipine/valsartan, 5/80 mg), patients with stage 3 AH Vamloset (amlodipine/valsartan, 5/160 mg). Therapy correction Vamloset (amlodipine/valsartan) in doses 5/160 mg, 10/160 mg and Co-Vamloset (amlodipine/valsartan/hydrochlorothiazide) in doses 10/160/12,5 mg, 10/160/25 mg (КРКА-RUS) was performed every 4 weeks according to provided schemes. At follow-up every 4 weeks the decision on necessity of antihypertensive treatment (AHT) correction were made by medical researcher in accordance with analysis of patients complaints, general condition and physical examination, results of office BP measurement, diary of BP self-control. In 40 patients in subgroup with additional assessment 24-hour BP monitoring, pulse wave velocity measurement, central BP evaluation, augmentation index calculation, and endothelium damage markers determination were performed. Results. Active phase of the study included 100 patients aged 59.510.9 years (59% female) suffering from AH for 83.48.4 months. The patients received treatment with study medication (safety population). The protocol population (sampling Per Protocol) included 80 patients who completed the study without severe protocol violation. At the moment of study entrance 83% of patients received AHT. In all patients treatment duration comprised 15.9 weeks. In Per Protocol population target office BP level was achieved by 90.0% (95% confidence interval 81.295.6%) of the patients. Overall clinical effectiveness (extremely high, very high, high, and sufficient) was achieved in 98.8% [95% confidence interval 93.2100%] of the patients. In group of patients with stage 2 AH target office BP level was achieved by 93.8% of patients, in group with stage 3 AH by 84.4% of patients. Mean BP change in study group was -32.2 mm Hg for SBP and -16.0 mm Hg for DBP. Among patients with stage 2 AH target office BP level was achieved by 93.8% of patients, with mean BP change -30,7 mm Hg for SBP and -15.5 mm Hg for DBP. In patients with stage 3 AH target BP levels were achieved in 84.4% of patients with mean BP change -34,6 mm Hg for SBP and -16.7 mm Hg for DBP. After 16 weeks of treatment in Full Analysis Set population with recovery of missed measures using Last Observation Carried Forward 40.2% of patients reached target BP levels according to BP self-control results. Considering the limitations of results evaluation this practice requires further assessment, standardization, and improvement. According to 24-hour BP monitoring reaults after 16 weeks of treatment 26.5% of patients achieved target BP daily profile (for patients from subgroup with additional assessment in Full Analysis Set population with recovery of missed measures using Last Observation Carried Forward), that indicates additional influence of studied AHT on the prognosis of patients with stages 23 AH. Conclusion. In clinical study VICTORY II Vamloset and Co-Vamloset optimal effectiveness and safety in patients with stage 2 and 3 arterial hypertension were shown.

Early Outcomes in the ROADSTER 2 Study of Transcarotid Artery Revascularization in Patients With Significant Carotid Artery Disease

Background and Purpose: Transcarotid artery revascularization (TCAR) is comprised of carotid artery stent placement with cerebral protection via proximal carotid artery clamping and reversal of cerebral arterial flow. The aim of the present study was to evaluate the safety and efficacy of TCAR performed by a broad group of physicians with variable TCAR experience. Methods: The ROADSTER 2 study is a prospective, open label, single arm, multicenter, postapproval registry for patients undergoing TCAR. Patients considered at high risk for complications from carotid endarterectomy with symptomatic stenosis ≥50% or asymptomatic stenosis ≥80% were included. The primary end point was procedural success, which encompassed technical success plus the absence of stroke, myocardial infarction, or death within the 30-day postoperative period. Secondary end points included technical success and individual/composite rates of stroke, death, and myocardial infarction (MI). All patients underwent independent neurological assessments before the procedure, within 24 hours, and at 30 days after TCAR. An independent clinical events committee adjudicated all major adverse events. Results: Between 2015 and 2019, 692 patients (Intent to Treat Population) were enrolled at 43 sites. Sixty cases had major protocol violations, leaving 632 patients adhering to the Food and Drug Administration-approved protocol (per-protocol population). The majority (81.2%) of operators were TCAR naïve before study initiation. Patients underwent TCAR for neurological symptoms in 26% of cases, and all patients had high-risk factors for carotid endarterectomy (anatomic-related 44%; physiological 32%; both 24%). Technical success occurred in 99.7% of all cases. The primary end point of procedural success rate in the Intent to Treat population was 96.5% (per-protocol 97.9%). The early postoperative outcomes in the Intent to Treat population included stroke in 13 patients (1.9%), death in 3 patients (0.4%), and MI in 6 patients (0.9%). The composite 30-day stroke/death rate was 2.3%, and stroke/death/MI rate was 3.2%. In the per-protocol population, there were strokes in 4 patients (0.6%), death in one patient (0.2%), and MI in 6 patients (0.9%) leading to a composite 30-day stroke/death rate of 0.8% and stroke/death/MI rate of 1.7%. Conclusions: TCAR results in excellent early outcomes with high technical success combined with low rates of postprocedure stroke and death. These results were achieved by a majority of operators new to this technology at the start of the trial. Adherence to the study protocol and peri-procedural antiplatelet therapy optimizes outcomes. Longer-term follow-up data are needed to confirm these early outcomes. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02536378.

SO086SNF472 CONSISTENTLY SLOWS PROGRESSION OF CORONARY CALCIFICATION IN PATIENTS ON HEMODIALYSIS: SUBGROUP ANALYSIS OF THE CALIPSO STUDY

Background and Aims In the CaLIPSO study, SNF472 significantly attenuated progression of coronary artery calcium (CAC) volume score compared with placebo. This pre-specified analysis examined the effect of SNF472 on CAC progression in key subgroups of patients in CaLIPSO. Method Patients with a CAC Agatston score of 100 to 3500 at baseline were randomized to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91), infused during hemodialysis (HD) thrice weekly for 52 weeks. Patients received standard of care therapy, including phosphate binders and calcimimetics as determined by investigator. The primary endpoint (change in log CAC volume score from baseline to week 52 in the combined dose groups vs placebo) was analyzed for patients who received SNF472 or placebo and had an evaluable CT scan post-randomization (modified ITT population). Sensitivity analysis was also performed for the per protocol population of patients that met entry criteria, received 80% of scheduled treatment, completed the study procedures, and had both a baseline and week 52 evaluable CT scan. The analysis plan pre-specified key subgroups: age, sex, diabetes, dialysis vintage, and arteriosclerotic cardiovascular disease (ASCVD), as well as baseline use of non-calcium phosphate binders, calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, or statins. Results Demographics and disease characteristics were similar across the treatment groups. Age (mean±SD) at baseline was 63.6±8.9 years and 39% of the patients were female; 62% had diabetes and 41% had prior ASCVD. Median dialysis vintage was 42.4 months; 33% had received hemodialysis for ≥5 years. Concomitant medications at baseline were: non-calcium phosphate binders, 62%; calcium-based phosphate binders, 28%; calcimimetics, 31%; activated vitamin D, 51%; warfarin, 8%; and statins, 64%. CAC volume progression was 11% for the combined dose groups and 20% for placebo (p=0.016). Treatment differences for CAC volume score progression from baseline to week 52 were similar across the subgroups (FIGURE). All interaction p-values were non-significant, and comparisons favored SNF472 vs placebo in each subgroup for both the modified ITT and per protocol population. Conclusion SNF472 treatment for 52 weeks attenuated CAC progression compared with placebo in all subgroups of the CaLIPSO study. These results support the potential benefit of SNF472 across a broad population of patients with cardiovascular calcification. Future studies are needed to determine the effects of SNF472 on cardiovascular events in patients receiving HD.

Safety and effectiveness of the Phoenix Atherectomy System in lower extremity arteries: Early and midterm outcomes from the prospective multicenter EASE study

Objectives To evaluate the novel Phoenix Atherectomy System as percutaneous treatment of de novo and restenotic infrainguinal arterial lesions. Methods This prospective, multicenter, nonrandomized investigational device exemption trial was conducted across 16 US and German centers between August 2010 and April 2013. Intention-to-treat enrollment was 128 patients (mean age: 71.8 years, 59% male) with 149 lesions (mean length: 34 mm, mean diameter stenosis: 89.5%), and the primary analysis per-protocol population consisted of 105 patients with 123 lesions. The primary efficacy endpoint, technical success, was the achievement of acute debulking with a post-atherectomy residual diameter stenosis ≤50% (before adjunctive therapy). The primary safety endpoint was the major adverse event (MAE) rate through 30 days. Results For the primary analysis per-protocol population, the rate of lesion technical success was 95.1% (117/123), with the lower limit of the 95% CI 90.6%, meeting the prospectively established target performance goal of ≥86%. After post-atherectomy adjunctive therapy, residual stenosis was ≤30% for 99.2% (122/123) of lesions (mean final diameter stenosis 10.5%). Improvement of ≥1 Rutherford class occurred for 74.5% of patients through 30 days and for 80% through six months. MAEs were experienced by 5.7% (6/105) of patients through 30 days (with the upper limit of the 95% CI 11.0%, meeting the target performance goal of <20%), and 16.8% through six months. Six-month freedom from TLR and TVR was 88.0% and 86.1%, respectively. Conclusions Based on the high rate of technical success and the low rates of MAEs through six months, the Phoenix Atherectomy System is safe and effective for the debulking of lower-extremity arterial lesions. ClinicalTrials.gov identifier NCT01541774