Clinical Endpoint Of Interest Research Articles

Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM. Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest. Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with T max generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (>10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action. Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

Plasma proteome landscape and impact of the circulatory proteome on clinical outcomes in metastatic prostate cancer.

237 Background: We performed plasma-based high-plex proteomic profiling for identifying classifiers of clinical outcomes in metastatic prostate cancer (PC). Olink Explore NGS-based proteome profiling platform was used for high-precision analysis of 736 cancer associated plasma proteins in plasma samples from non-metastatic stage prostate cancer (PC), metastatic hormone-sensitive PC (mHSPC) and metastatic castrate resistant PC (mCRPC) states. Methods: Plasma was collected prospectively in a cohort of 108 PC patients (24 with non-metastatic PC; 28 mHSPC; 56 mCRPC of which 37 patients were collected before starting any mCRPC treatments). Proteomic data were generated with Proximity Extension Assay (PEA) on the Olink platform from 100 µL plasma per sample. Levels of 736 cancer-associated protein assays were denoted as normalized protein expression (NPX) units through a QC and normalization process developed and provided by Olink. Data generation of NPX consists of normalization to the extension control, log2 -transformation, and level adjustment using the plate control (plasma sample). Temporal trends of differentially expressed assays in non-metastatic PC, mHSPC and mCRPC states were identified using linear mixed effects model (FDR with Benjamini-Hochberg (BH) adjustment; q-value<0.05, R version 4.1.2.). Clinical outcomes included in mCRPC state overall survival (calculated as time from turning mCRPC to death) and in mHSPC early failure of ADT-based therapies defined as progression within 12.5 months. Cox proportional hazard regression was performed for proteins associated with mHSPC and mCRPC states and clinical endpoint of interest. Results: After BH adjustments, 105 protein assays were differentially expressed across non-metastatic, mHSPC and mCRPC states of which 73 assays differed between non-metastatic and metastatic states (q<0.05). 83/105 assays differed between mHSPC and mCRPC states (q<0.05). Of the 83 plasma proteins, 77 were over-expressed in mCRPC. 19/37 mCRPC patients who had collections performed before mCRPC treatments had died. The median time to death was 29 months (Range: 1.9-119 mths). After adjustment for serum Alkaline phosphatase (ALP) levels in these 37 mCRPC patients 32/77 were significantly associated with overall survival. After performing an enrichment analysis the oxidative phosphorylation pathway with specific proteins assays (IMMT, COX5B and FXN, p = 5.1e-4, FDR = 2.55 e-2) were significantly overexpressed in patients with poor survival. Conclusions: A global plasma proteomic profiling of cancer related proteins revealed significant differences in expression in different states of cancer progression. Overexpressed proteins related to oxidative phosphorylation pathway in mCRPC in specific are associated with poor survival.

Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and Molnupiravir

Some patients treated with nirmatrelvir-ritonavir have experienced rebound of COVID-19 infections and symptoms; however, data are scarce on whether viral rebound also occurs in patients with COVID-19 receiving or not receiving molnupiravir. To examine the incidence of viral rebound in patients with COVID-19 who were treated with the oral antiviral agents nirmatrelvir-ritonavir and molnupiravir. This cohort study identified 41 255 patients with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values measured. Patients were followed up until the occurrence of the clinical end point of interest, death, date of data retrieval (July 31, 2022), or up to 30 days of follow-up, whichever came first. Molnupiravir or nirmatrelvir-ritonavir treatment. Viral rebound, defined as a Ct value greater than 40 that decreased to 40 or less. Of 12 629 patients (mean [SD] age, 65.4 [20.9] years; 6624 [52.5%] male), 11 688 (92.5%) were oral antiviral nonusers, 746 (5.9%) were molnupiravir users, and 195 (1.5%) were nirmatrelvir-ritonavir users. Compared with nonusers, oral antiviral users were older, had more comorbidities, and had lower complete vaccination rates. The mean (SD) baseline Ct value was slightly higher in nirmatrelvir-ritonavir users (22.2 [6.0]) than nonusers (21.0 [5.4]) and molnupiravir users (20.9 [5.4]) (P = .04). Viral rebound occurred in 68 nonusers (0.6%), 2 nirmatrelvir-ritonavir users (1.0%), and 6 molnupiravir users (0.8%). Among 76 patients with viral rebound, 12 of 68 nonusers, 1 of 6 molnupiravir users, and neither of the nirmatrelvir-ritonavir users died of COVID-19. In this cohort study, viral rebound was uncommon in patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated with increased risk of mortality. Given these findings, novel oral antivirals should be considered as a treatment for more patients with COVID-19 in the early phase of the infection.

Synthesizing evidence from clinical trials with dynamic interactive argument trees

BackgroundEvidence-based medicine propagates that medical/clinical decisions are made by taking into account high-quality evidence, most notably in the form of randomized clinical trials. Evidence-based decision-making requires aggregating the evidence available in multiple trials to reach –by means of systematic reviews– a conclusive recommendation on which treatment is best suited for a given patient population. However, it is challenging to produce systematic reviews to keep up with the ever-growing number of published clinical trials. Therefore, new computational approaches are necessary to support the creation of systematic reviews that include the most up-to-date evidence.We propose a method to synthesize the evidence available in clinical trials in an ad-hoc and on-demand manner by automatically arranging such evidence in the form of a hierarchical argument that recommends a therapy as being superior to some other therapy along a number of key dimensions corresponding to the clinical endpoints of interest. The method has also been implemented as a web tool that allows users to explore the effects of excluding different points of evidence, and indicating relative preferences on the endpoints.ResultsThrough two use cases, our method was shown to be able to generate conclusions similar to the ones of published systematic reviews. To evaluate our method implemented as a web tool, we carried out a survey and usability analysis with medical professionals. The results show that the tool was perceived as being valuable, acknowledging its potential to inform clinical decision-making and to complement the information from existing medical guidelines.ConclusionsThe method presented is a simple but yet effective argumentation-based method that contributes to support the synthesis of clinical trial evidence. A current limitation of the method is that it relies on a manually populated knowledge base. This problem could be alleviated by deploying natural language processing methods to extract the relevant information from publications.

Association Between Right Ventricular Dysfunction and Adverse Outcomes in Peripartum Cardiomyopathy: Insights From the BRO-HF Quebec Cohort Study

BackgroundPeripartum cardiomyopathy (PPCM) is associated with severe morbidity and mortality, and the significance of right ventricular (RV) involvement is unclear. We sought to determine whether RV systolic dysfunction or dilatation is associated with adverse clinical outcomes in women with PPCM. MethodsWe conducted a multicentre retrospective cohort study examining the association between echocardiographic RV systolic dysfunction or dilatation at the time of PPCM diagnosis and clinical outcomes. Clinical endpoints of interest were the need for mechanical support, recovery of left ventricular ejection fraction at follow-up, and a combined endpoint of hospitalization for heart failure, cardiac transplant, or death. ResultsA total of 67 women, median age 30 years (interquartile range: 7), were diagnosed with PPCM between 1994 and 2015 in 17 participating centres. Twin pregnancies occurred in 11%; 62% of women were multiparous; and 24% had preeclampsia. RV systolic function was impaired in 18 (27%) and dilated in 8 (12%). Seven women required ventricular assistance, and 8 experienced the composite outcome during follow-up (25 [interquartile range 61] months). RV dysfunction was associated with the need for mechanical support (odds ratio 10.10 (95% confidence interval: 1.86-54.81), P = 0.007), but neither RV dysfunction nor dilatation was associated with left ventricular ejection fraction recovery, the need for cardiac transplant, heart failure hospitalization, or death. ConclusionsRV dysfunction is associated with the need for mechanical support in women with PPCM. These findings may improve risk stratification of complications and clinical management.

Therapeutic versus prophylactic anticoagulation in patients with COVID-19: a meta-analysis of randomised controlled trials

Abstract Funding Acknowledgements Type of funding sources: None. Background Several systematic reviews and meta-analyses have been conducted to evaluate the effects of anticoagulation on patients admitted with coronavirus infectious disease 2019 (COVID-19). However, since most of them consist of observational studies, the optimal dose still remains controversial. Purpose The purpose of this study was to investigate the efficacy and safety of therapeutic anticoagulation compared with prophylactic anticoagulation in patients admitted with COVID-19. Methods A meta-analysis was conducted on randomised controlled trials (RCTs) to minimise bias. PubMed and the Cochrane Central Register of Controlled Trials were queried for the terms "covid-19," "(anticoagulation OR thromboprophylaxis)," and "randomised." The same terms or relevant studies were also queried on the website of the ClinicalTrials.gov and relevant reviews. The clinical endpoints of interest were all-cause death, thromboembolism, and major bleeding. Pooled estimates were calculated using a random-effects model. Results A total of 7 RCTs were included in this study. The risk of thromboembolism was lower (odds ratio (OR) 0.54; 95% confidence interval (CI) 0.41-0.73; p < 0.001) and the risk of major bleeding was higher (OR 1.87; 95% CI 1.21-2.90; p = 0.005) in the therapeutic anticoagulation group than in the prophylactic anticoagulation group. On the other hand, the risk of all-cause death was similar (OR 0.92; 95% CI 0.65-1.31; p = 0.65) between the 2 groups. In a subgroup analysis, the risk of thromboembolism was also lower in the therapeutic anticoagulation group compared with the prophylactic anticoagulation group both in moderately and severely ill patients, respectively. However, the risk of major bleeding was more likely to higher (OR 1.85; 95% CI 0.98-3.49; p = 0.06) in the therapeutic anticoagulation group than the prophylactic anticoagulation group only in severely ill patients. Conclusions Therapeutic anticoagulation is associated with a lower risk of thromboembolism and a higher risk of major bleeding compared to prophylactic anticoagulation in patients hospitalised with COVID-19. Therapeutic anticoagulation may be more beneficial for moderately ill patients.

Impact of L-carnitine in narcolepsy treatment: a systematic review on the effectiveness and safety.

IntroductionStudies have shown that narcolepsy patients may present with low serum acylcarnitine levels, demonstrating a dysfunctional beta fatty acid oxidation pathway in these patients.ObjectiveEvaluate the therapeutic efficacy of L-carnitine as a treatment for narcolepsy patients.MethodsThis study runned in form of systematic review. The terms used for the search: (“narcolepsy”[MeSH Terms] OR “narcolepsy”[All Fields]) AND (“carnitine”[MeSH Terms] OR “carnitine”[All Fields] OR “l carnitine”[All Fields]). Were included all surveys published until January 2021, with the diagnosis of narcolepsy, that performed drug treatment with I-carnitine. The clinical endpoints of interest were: excessive daytime sleepiness, dissociative REM sleep manifestations: cataplexy, sleep paralysis, hypnagogic hallucinations, and early REM sleep (REM sleep naps, SOREMP).ResultsL-carnitine was found to be well-tolerated and without side effects in all surveys, at dosages ranging from 500 to 510 mg/day. Newborns did not present complications during delivery.ConclusionThis study corroborates the efficacy and good tolerability of L-carnitine therapy as a treatment for patients with narcolepsy, including during pregnancy.

Treatment outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) with sarcomatoid and/or rhabdoid (S/R) features after progressive disease (PD) on immune checkpoint therapy (ICT): The MD Anderson Cancer Center experience.

351 Background: S/R mRCC is an aggressive disease that is associated with improved response to ICT. Studies performed prior to the approval of ICT demonstrated poor outcomes of S/R RCC with VEGF targeted therapies (TT). Here, we report outcomes of pts with S/R mRCC treated with VEGF TT after PD on ICT. Methods: We retrospectively reviewed the records of pts with mRCC with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S+R) features who received VEGF TT after PD on ICT. Clinical endpoints of interest were time on VEGF TT and OS from treatment initiation. Directed acyclic graphs were used to identify confounders for adjustment in regression models. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using multivariable Cox regression. Multivariable models adjusted for epithelial histology, IMDC risk, prior VEGF TT, and inclusion of cabozantinib in the post-ICT VEGF TT regimen. Results: 57 pts with metastatic S/R RCC (52 with clear cell and 5 with non-clear cell histology) received a VEGF TT after PD on ICT. 46% of pts received a VEGF TT prior to ICT. After PD on ICT, 67% of pts had IMDC intermediate-risk disease; the most commonly used VEGF TT were cabozantinib (44%), either sunitinib, pazopanib, or axitinib (24%), and a VEGF TT in combination with an ICT (21%). Pts with R RCC had significantly longer time on VEGF TT compared with S RCC (adjusted HR = 0.45, 95% CI 0.21-0.94, p = 0.034), whereas the OS comparison was inconclusive (adjusted HR = 0.77, 95% CI 0.36-1.62, p = 0.486). IMDC risk classification following ICT progression was predictive of OS (adjusted HR = 2.22, 95% CI 1.07-4.61, p = 0.032), whereas, its association with time on VEGF TT was less conclusive (adjusted HR = 1.78, 95% CI 0.88-3.60, p = 0.107). Conclusions: Patients with S/R mRCC derive clinical benefit from VEGF TT after progression on ICT, and it is similar to the benefit previously described for patients without S/R features. Our findings suggest that the type of S/R features present and IMDC risk score inform the clinical benefit that VEGF TT will produce in this setting.[Table: see text]

Optical coherence tomography versus angiography and intravascular ultrasound to guide coronary stent implantation: A systematic review and meta-analysis.

Optical coherence tomography (OCT) is an adjunct to angiography-guided coronary stent placement. However, in the absence of dedicated, appropriately powered randomized controlled trials, the impact of OCT on clinical outcomes is unclear. To conduct a systematic review and meta-analysis of all available studies comparing OCT-guided versus angiography-guided and intravascular ultrasound (IVUS)-guided coronary stent implantation. MEDLINE and Cochrane Central were queried from their inception through July 2022 for all studies that sought to compare OCT-guided percutaneous coronary intervention (PCI) to angiography-guided and IVUS-guided PCI. The primary endpoint was minimal stent area (MSA) compared between modalities. Clinical endpoints of interest were all-cause and cardiovascular mortality, major adverse cardiovascular events (MACE), myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and stent thrombosis (ST). Risk ratios (RRs) and mean differences (MDs) with their corresponding 95% confidence intervals (CIs) were pooled using a random-effects model. Thirteen studies (8 randomized control trials and 5 observational studies) enrolling 6312 participants were included. OCT was associated with a strong trend toward increased MSA compared to angiography (MD = 0.36, p = 0.06). OCT-guided PCI was also associated with a reduction in the incidence of all-cause mortality [RR = 0.59, 95% CI (0.35, 0.97), p = 0.04] and cardiovascular mortality [RR = 0.41, 95% CI (0.21, 0.80), p = 0.009] compared with angiography-guided PCI. Point estimates favored OCT relative to angiography in MACE [RR = 0.75, 95% CI (0.47, 1.20), p = 0.22] and MI [RR = 0.75, 95% CI (0.53, 1.07), p = 0.12]. No differences were detected in ST [RR = 0.71, 95% CI (0.21, 2.44), p = 0.58], TLR [RR = 0.71, 95% CI (0.17, 3.05), p = 0.65], or TVR rates [RR = 0.89, 95% CI (0.46, 1.73), p = 0.73]. Compared with IVUS guidance, OCT guidance was associated with a nonsignificant reduction in the MSA (MD = -0.16, p = 0.27). The rates of all-cause and cardiovascular mortality, MACE, MI, TLR, TVR, or ST were similar between OCT-guided and IVUS-guided PCI. OCT-guided PCI was associated with reduced all-cause and cardiovascular mortality compared to angiography-guided PCI. These results should be considered hypothesis generating as the mechanisms for the improved outcomes were unclear as no differences were detected in the rates of TLR, TVR, or ST. OCT- and IVUS-guided PCI resulted in similar post-PCI outcomes.

Assurance in vaccine efficacy clinical trial design based on immunological responses.

The assurance of a future clinical trial is a key quantitative tool for decision‐making in drug development. It is derived from prior knowledge (Bayesian approach) about the clinical endpoint of interest, typically from previous clinical trials. In this paper, we examine assurance in the specific context of vaccine development, where early development (Phase 2) is often based on immunological endpoints (e.g., antibody levels), while the confirmatory trial (Phase 3) is based on the clinical endpoint (very large sample sizes and long follow‐up). Our proposal is to use the Phase 2 vaccine efficacy predicted by the immunological endpoint (using a model estimated from epidemiological studies) as prior information for the calculation of the assurance.

Nabiximols in Chronic Neuropathic Pain: A Meta-Analysis of Randomized Placebo-Controlled Trials

Pooled analysis of nabiximols and placebo in randomized controlled studies (RCTs) of chronic neuropathic pain. Systematic review and meta-analysis. A systematic literature search was conducted to identify double-blind placebo-controlled RCTs of nabiximols for chronic neuropathic pain. The clinical endpoint of interest was change from baseline in mean pain score on 11-point numerical rating scales. Mean difference (MD) and standardized mean difference (SMD, Hedges' g) were calculated using fixed effect (FE) and random effects (RE) models. Strength of evidence was assessed using the Cochrane Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Risk of bias was assessed using the revised Cochrane risk-of-bias tool (RoB 2). Nine RCTs with 1289 participants were included. Quality of evidence (GRADE) was moderate. One study had a high risk of bias (RoB 2) and five had some concerns. For the pooled endpoint of change from baseline in mean pain score, nabiximols was superior to placebo, with a MD of - 0.40 (95% confidence interval [CI]: -0.59 to - 0.21; FE, p < 0.0001) or - 0.44 (95% CI: -0.70 to - 0.19; RE, p = 0.0006). A SMD of - 0.21 (95% CI: -0.32 to - 0.10; FE) or - 0.26 (95% CI: -0.42 to - 0.10; RE) indicated an incremental benefit over background analgesia. Results in favor of nabiximols were maintained in sensitivity analyses. Nabiximols was superior to placebo for reduction of chronic neuropathic pain, with a small effect size. Larger RCTs designed to assess the effect of nabiximols in neuropathic pain are required to reach more definitive conclusions.

The effect of smoking on COVID-19 severity: A systematic review and meta-analysis.

Various comorbidities represent risk factors for severe coronavirus disease 2019 (COVID‐19). The impact of smoking on COVID‐19 severity has been previously reported in several meta‐analyses limited by small sample sizes and poor methodology. We aimed to rigorously and definitively quantify the effects of smoking on COVID‐19 severity. MEDLINE, Embase, CENTRAL, and Web of Science were searched between 1 December 2019 and 2 June 2020. Studies reporting smoking status of hospitalized patients with different severities of disease and/or at least one clinical endpoint of interest (disease progression, intensive care unit admission, need for mechanical ventilation, and mortality) were included. Data were pooled using a random‐effects model. This study was registered on PROSPERO: CRD42020180920. We analyzed 47 eligible studies reporting on 32 849 hospitalized COVID‐19 patients, with 8417 (25.6%) reporting a smoking history, comprising 1501 current smokers, 5676 former smokers, and 1240 unspecified smokers. Current smokers had an increased risk of severe COVID‐19 (risk ratios [RR]: 1.80; 95% confidence interval [CI]: 1.14‐2.85; P = .012), and severe or critical COVID‐19 (RR: 1.98; CI: 1.16‐3.38; P = .012). Patients with a smoking history had a significantly increased risk of severe COVID‐19 (RR: 1.31; CI: 1.12‐1.54; P = .001), severe or critical COVID‐19 (RR: 1.35; CI: 1.19‐1.53; P < .0001), in‐hospital mortality (RR: 1.26; CI: 1.20‐1.32; P < .0001), disease progression (RR: 2.18; CI: 1.06‐4.49; P = .035), and need for mechanical ventilation (RR: 1.20; CI: 1.01‐1.42; P = .043). Patients with any smoking history are vulnerable to severe COVID‐19 and worse in‐hospital outcomes. In the absence of current targeted therapies, preventative, and supportive strategies to reduce morbidity and mortality in current and former smokers are crucial.

Evaluating futility of a binary clinical endpoint using early read-outs.

Interim analyses are routinely used to monitor accumulating data in clinical trials. When the objective of the interim analysis is to stop the trial if the trial is deemed futile, it must ideally be conducted as early as possible. In trials where the clinical endpoint of interest is only observed after a long follow-up, many enrolled patients may therefore have no information on the primary endpoint available at the time of the interim analysis. To facilitate earlier decision-making, one may incorporate early response data that are predictive for the primary endpoint (eg, an assessment of the primary endpoint at an earlier time) in the interim analysis. Most attention so far has been given to the development of interim test statistics that include such short-term endpoints, but not to decision procedures. Existing tests moreover perform poorly when the information is scarce, eg, due to rare events, when the cohort of patients with observed primary endpoint data is small, or when the short-term endpoint is a strong but imperfect predictor. In view of this, we develop an interim decision procedure based on the conditional power approach that utilizes the short-term and long-term binary endpoints in a framework that is expected to provide reliable inferences, even when the primary endpoint is only available for a few patients, and has the added advantage that it allows the use of historical information. The operational characteristics of the proposed procedure are evaluated for the phase III clinical trial that motivated this approach, using simulation studies.

P3733Long term follow-up after percutaneous closure of patent foramen ovale for secondary prevention of stroke

Abstract Background Recent randomized trials have demonstrated the superiority of percutaneous patent foramen ovale (PFO) closure for the secondary prevention of stroke compared to antithrombotic therapy. However, real-world data on long-term outcomes after percutaneous PFO closure are scarce. Purpose To describe real-world long-term outcomes following PFO percutaneous closure and the impact of the use of intracardiac echocardiography under local anesthesia for the procedure Methods All consecutive patients undergoing PFO closure in a single high-volume tertiary center from January 2006 to December 2018, for secondary prevention of stroke, transient ischemic attack (TIA) or any other paradoxical arterial embolism were prospectively studied. A systematic contrast transthoracic echocardiography (TTE) was performed 3 months after closure. Clinical endpoints of interest were the occurrence of death, stroke or transient ischemic attack, as defined in previous randomized trials. Results Of the 242 closure procedures performed, a total of 208 (86.3%) were performed in secondary prevention of stroke, TIA or paradoxical arterial embolism (mean age 49.8±12.7 years; 62.0% male). An atrial septal aneurysm and a large shunt were present in 137 (66.8%) and 172 (84.7%) patients, respectively. General anesthesia associated with transesophageal echocardiography was initially used in all patients with a temporal trend towards the use of local anesthesia associated with either intracardiac echocardiography (Viewflex catheter, Abbott) in 23 more cases or micro transesophageal probe in 7 cases, without periprocedural complications. Discharge medication comprised of dual antiplatelet therapy, oral anticoagulation and single antiplatelet therapy in 80.7%, 16.8% and 2.5% of the patients, respectively. Contrast TTE with Valsalva maneuver was performed at a mean delay of 3.2±0.7 months after intervention and found no or minimal residual shunt in 87.0% of patients. Clinical follow-up was available up to 12.8 years (mean 2.1±3.0 years). A total of 3 patients died from cancer or unknown cause while stroke and TIA occurred in 2 and 1 patients, respectively. Event rate for death was 0.69 events per 100 patients-years. The event rates for stroke, TIA and stroke or TIA were 0.46, 0.23 and 0.70 events per 100 patients-year of observation, respectively, which compare favorably with reported outcomes following percutaneous closure in randomized clinical trials (Figure). Conclusion In an experienced center, percutaneous PFO closure appears to be a safe procedure providing adequate protection against recurrent strokes over a long follow-up. Acknowledgement/Funding ACTION study group

Clinical Outcomes of Spatially Fractionated GRID Radiotherapy in the Treatment of Bulky Tumors of the Head and Neck.

ObjectivesThe clinical outcomes of patients treated with spatially fractionated GRID radiotherapy (SFGRT) for bulky tumors of the head and neck at a single institution were evaluated retrospectively. Endpoints of interest included tumor response, symptom improvement, treatment tolerance, and adverse events.MethodsInstitutional review board approval was obtained prior to study initiation. The institutional database was queried for patients with tumors of the head and neck treated with SFGRT between August 2007 and April 2015. Medical records of identified patients were reviewed for treatment details and clinical endpoints of interest. SFGRT was delivered in one fraction of 15 gray (Gy) or 20 Gy; 6 megavolt (MV) or 18 MV photon beams were passed through a multileaf collimator (MLC)-based or brass GRID template. All patients had a planned course of conventionally-fractionated external beam radiotherapy (EBRT) to begin on the day following SFGRT delivery.ResultsTwenty-one consecutive patients meeting study criteria were identified. The most common tumor histology was squamous cell carcinoma. Median patient age was 59 years (range 13 - 83 years); median maximum tumor dimension was 9.5 centimeters (cm) (range 5.0 - 25.0 cm). Fifteen patients (71.4%) completed their full course of EBRT. Twelve patients were treated with palliative intent for local tumor symptoms, of which 54.5% experienced some degree of symptom improvement. Of nine patients treated with curative intent, 44.4% achieved a clinical complete response (CR). Concurrent chemotherapy was administered in 12 patients, with all patients being treated having definitively received chemotherapy. Radiation Therapy Oncology Group (RTOG) grade three or higher skin toxicity occurred in five patients; no grade five events were reported.ConclusionsOur institutional experience suggests that SFGRT is a feasible treatment option for the palliative or definitive management of large tumors of the head and neck. In combination with EBRT, SFGRT can provide timely symptom management and improve patient quality of life in the palliative setting. In the definitive setting, the addition of chemotherapy to SFGRT and EBRT can result in an excellent clinical response. Treatment toxicity was found to be within an acceptable range. When considering SFGRT for patients with these challenging presentations, careful patient selection is needed to identify those who will likely tolerate a full course of EBRT following SFGRT, as these patients are most likely to receive maximal benefit from SFGRT treatment. More data on the feasibility and efficacy of this radiation modality will be helpful for continued optimization of SFGRT delivery and patient selection.

Predictive probability of success using surrogate endpoints.

The predictive probability of success of a future clinical trial is a key quantitative tool for decision-making in drug development. It is derived from prior knowledge and available evidence, and the latter typically comes from the accumulated data on the clinical endpoint of interest in previous clinical trials. However, a surrogate endpoint could be used as primary endpoint in early development and, usually, no or limited data are collected on the clinical endpoint of interest. We propose a general, reliable, and broadly applicable methodology to predict the success of a future trial from surrogate endpoints, in a way that makes the best use of all the available evidence. The predictions are based on an informative prior, called surrogate prior, derived from the results of past trials on one or several surrogate endpoints. If available, in a Bayesian framework, this prior could be combined with data from past trials on the clinical endpoint of interest. Two methods are proposed to address a potential discordance between the surrogate prior and the data on the clinical endpoint. We investigate the patterns of behavior of the predictions in a comprehensive simulation study, and we present an application to the development of a drug in Multiple Sclerosis. The proposed methodology is expected to support decision-making in many different situations, since the use of predictive markers is important to accelerate drug developments and to select promising drug candidates, better and earlier.

A comparative analysis of clinical outcomes and disposable costs of different catheter ablation methods for the treatment of atrioventricular nodal reentrant tachycardia.

BackgroundCatheter ablation of atrioventricular nodal reentrant tachycardia (AVNRT) is a commonly performed electrophysiology (EP) procedure. Few data exist comparing conventional (CONV) versus novel ablation strategies from both clinical and direct cost perspectives. We sought to investigate the disposable costs and clinical outcomes associated with three different ablation methodologies used in the ablation of AVNRT.MethodsWe performed a retrospective review of AVNRT ablations performed at Augusta University Medical Center from 2006 to 2014. A total of 183 patients were identified. Three different ablation techniques were compared: CONV manual radiofrequency (RF) (n=60), remote magnetic navigation (RMN)-guided RF (n=67), and cryoablation (CRYO) (n=56).ResultsBaseline demographics did not differ between the three groups except for a higher prevalence of cardiomyopathy in the RMN group (p<0.01). The clinical end point of interest was recurrent AVNRT following the index ablation procedure. A significantly higher number of recurrent AVNRT cases occurred in the CRYO group as compared to CONV and RMN (p=0.003; OR =7.75) groups. Cost-benefit analysis showed both CONV and RMN to be dominant compared to CRYO. Cost-minimization analysis demonstrated the least expensive ablation method to be CONV (mean disposable catheter cost = CONV US$2340; CRYO US$3515; RMN US$5190). Despite comparable clinical outcomes, the incremental cost of RMN over CONV averaged US$3094 per procedure.ConclusionAVNRT ablation using either CONV or RMN techniques is equally effective and associated with lower AVNRT recurrence rates than CRYO. CONV ablation carries significant disposable cost savings as compared to RMN, despite similar efficacy.

Evaluating principal surrogate markers in vaccine trials in the presence of multiphase sampling.

This article focuses on the evaluation of vaccine-induced immune responses as principal surrogate markers for predicting a given vaccine's effect on the clinical endpoint of interest. To address the problem of missing potential outcomes under the principal surrogate framework, we can utilize baseline predictors of the immune biomarker(s) or vaccinate uninfected placebo recipients at the end of the trial and measure their immune biomarkers. Examples of good baseline predictors are baseline immune responses when subjects enrolled in the trial have been previously exposed to the same antigen, as in our motivating application of the Zostavax Efficacy and Safety Trial (ZEST). However, laboratory assays of these baseline predictors are expensive and therefore their subsampling among participants is commonly performed. In this article, we develop a methodology for estimating principal surrogate values in the presence of baseline predictor subsampling. Under a multiphase sampling framework, we propose a semiparametric pseudo-score estimator based on conditional likelihood and also develop several alternative semiparametric pseudo-score or estimated likelihood estimators. We derive corresponding asymptotic theories and analytic variance formulas for these estimators. Through extensive numeric studies, we demonstrate good finite sample performance of these estimators and the efficiency advantage of the proposed pseudo-score estimator in various sampling schemes. We illustrate the application of our proposed estimators using data from an immune biomarker study nested within the ZEST trial.

Incomplete Cross-Resistance Between Taxanes for Advanced Urothelial Carcinoma: Implications for Clinical Practice and Trial Design

BackgroundTaxanes such as paclitaxel and docetaxel are commonly used for second- or third-line salvage systemic therapy for metastatic UC. Although trials have generally excluded previous exposure to taxanes when using a taxane in a salvage therapy trial, taxanes might not be completely cross-resistant. Hence, we aimed to study outcomes with docetaxel after previous paclitaxel and the reverse sequence, to identify the level of cross-resistance between these taxanes. Patients and MethodsData from a randomized phase II trial that compared salvage therapy with docetaxel combined with either placebo or vandetanib for advanced UC were analyzed. Both arms were combined for analysis because no differences in any outcomes were observed. Data were also requested from institutions for patients who received paclitaxel after previous docetaxel treatment. Descriptive statistics were used to summarize patient and treatment characteristics and outcomes. The primary clinical end point of interest was overall survival (OS). ResultsOf 148 patients who received docetaxel with either vandetanib or placebo, 21 had received previous paclitaxel treatment. No difference in OS, progression-free survival, or response rate was observed with docetaxel based on previous paclitaxel treatment after adjusting for known prognostic factors. Among the 8 patients who received paclitaxel after previous docetaxel treatment, partial response was observed in 1 patient (12.5%) and stable disease in 2 patients (25%). ConclusionDocetaxel treatment after previous paclitaxel treatment and the reverse sequence demonstrates activity in advanced UC. There is no strong evidence to disallow patients with previous exposure to a taxane to enroll in a clinical trial involving another taxane.

Carotid Intima-media Thickness

Evidence-based medicine requires us to use pharmacological agents that have been tested and that have been showed to reduce the disease in that particular group of affected patients. The choice of the efficacy endpoint is one of the most controversial issues in designing the trials. To reduce the high economic costs resulting by the large-scale trials design and implementation, the substitution of the primary endpoints with a surrogate one, is an optimal opportunity. Carotid intima-media thickness is considered an excellent predictor of cardiovascular events, and it is also seen as a perfect model of surrogate endpoint for pharmacological studies. However, the results from studies using it as a surrogate endpoints could lead to erroneous conclusions and could lead marketing of products with limited or doubt effectiveness on cardiovascular prevention. Studies showed that many interventions targeting the Carotid intima-media thickness not impact the final clinical endpoints of interest, whereas low-density lipoprotein cholesterol level is an excellent biomarker because it can predict the cardiovascular outcomes and interventions therapy can efficaciously reduce it.