Interactive statistical monitoring to optimize review of potential clinical trial issues during study conduct.

Background: Statistical monitoring involves the review of prospective study data collected in participating sites to detect intra/inter patients and sites inconsistencies. We report methods and results of statistical monitoring in a phase IV clinical trial. Method: PRO-MSACTIVE is a study evaluating ocrelizumab in active relapsing multiple sclerosis (RMS) patients in France. Specific statistical methods (volcano plots, mahalanobis distance, funnel plot …) have been applied to a SDTM database to detect potential issues. R-Shiny application was developed to generate an interactive web application in order to ease site and/or patients identification during statistical data review meetings. Results: The PRO-MSACTIVE study enrolled 422 patients in 46 centers between July 2018 and August 2019. Three data review meetings were held between April and October 2019 and 14 standard and planned tests were run on study data, with a total of 15 (32.6%) sites identified as needing review or investigation. Overall 36 findings were identified during the meetings: duplicate records, outliers, inconsistent delays between dates. Conclusion: Statistical monitoring is useful to identify unusual or clustered data patterns that might be revealing issues that could impact the data integrity and/or may potentially impact patients' safety. With anticipated and appropriate interactive data visualization, early signals can easily be identified or reviewed by the study team and appropriate actions be set up and assigned to the most appropriate function for a close follow-up and resolution. Interactive statistical monitoring is time consuming to initiate using R-Shiny, but is time saving after the 1st data review meeting (DRV).(ClinicalTrials.gov identifier: NCT03589105; EudraCT identifier: 2018-000780-91).

Efficacy, safety and patient reported outcomes in patients with active relapsing multiple sclerosis treated with ocrelizumab: Final results from the PRO-MSACTIVE study.

BACKGROUND: Ocrelizumab, a humanized anti-CD20 monoclonal antibody, has been approved in Europe for the treatment of adult patients with active relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), on the basis of previous phase III studies. However, limited data were available on ocrelizumab efficacy in RMS according to the Lublin definition of activity (clinical and/or imaging features) used in the current drug label. The PRO-MSACTIVE study was thus designed to provide additional data on ocrelizumab efficacy according to this definition, and also on safety and patient reported outcomes (PROs). METHODS: PRO-MSACTIVE is a national, multicenter, open-label, single-arm phase IV French study, conducted in patients with active RMS (relapsing-remitting multiple sclerosis, RRMS, or secondary progressive multiple sclerosis, SPMS). The primary endpoint, which was assessed at week (W) 48, was defined as the proportion of patients free of disease activity (defined by no relapses and no T1 gadolinium-enhancing nor new and/or enlarging T2 lesions using brain MRI). Disease activity, disability and PROs using 6 questionnaires for disease severity, quality of life, impact on work productivity, and treatment satisfaction were described at W24 and W48. Adverse events were described until W72. RESULTS: Among the 422 analyzed patients (RRMS: 376, SPMS: 46), 63.3% (95% CI [58.5%; 67.9%]) were free of disease activity at W48 (RRMS: 62.2% [57.1%; 67.2%], SPMS: 71.7% [56.5%; 84.0%]). A total of 358 patients (84.8%; RRMS: 84.6%, SPMS: 87.0%) were relapse-free up to W48, and the overall adjusted annualized relapse rate was 0.14 (RRMS: 0.15, SPMS: 0.09). Overall, 67.8% of patients (RRMS: 66.8%, SPMS: 76.1%) had no evidence of MRI activity (no T1 gadolinium-enhancing lesions [83.4%] and no new/enlarging T2 lesions [75.1%]); 58.5% of patients (RRMS: 57.7%, SPMS: 65.2%) achieved No Evidence of Disease Activity (NEDA: no relapses, no confirmed disability progression, and no MRI activity) at W48. All PRO scores were stable between the first dose of ocrelizumab and W48 and better outcomes were seen for patients having an EDSS score ≥4. Overall, 89.3% of patients reported adverse events, 62.3% adverse events assessed as related to ocrelizumab, and 8.5% serious adverse events. No serious infusion-related reactions, opportunistic infections, progressive multifocal leukoencephalopathy, nor deaths were reported. No new safety signal was identified. CONCLUSION: These data confirm the efficacy of ocrelizumab in a pragmatic setting and its favorable benefit-risk profile in patients with RMS. (ClinicalTrials.gov identifier: NCT03589105; EudraCT identifier: 2018-000780-91).

FRESC: French Real world Extensive stage SCLC Cohorts: A retrospective study on patient characteristics and treatment strategy based on KBP-2010.

OBJECTIVES: FRESC reanalyzed extensive-stage small-cell lung cancer (ES-SCLC) patient data from the French KBP-2010 cohort to describe the characteristics and therapeutic management of ES-SCLC and provide real-world estimates of survival. METHODS: A target population of first line (1L) ES-SCLC was identified at initial diagnosis in KBP-2010 (KBP population, N = 796). A KBP-2010 subpopulation was defined as patients who also met the IMpower133 clinicaltrial PS ≤ 1 inclusion criteria (KBP-PS_0/1 population, N = 394). Subgroups were defined according to the 1L ES-SCLC chemotherapy regimens: carboplatin or cisplatin with etoposide (Carb-E or Cisp-E subgroups). RESULTS: The vast majority of KBP populations exhibited stage IV ES-SCLC (84.9%) at initial diagnosis. Median age was 66 years; patients were mostly male and smokers. Patients receiving Cisp + Eto were younger (median age 61 years [55.0-67.0]) and fitter (25.5% had PS ≥ 2) than those receiving Carb + Eto (71 years [62.5-77.5]; 44.1%had PS ≥ 2). Median overall survival (OS) of chemotherapy-treated 1L ES-SCLC patients varied from 7.0 months [95% CI, 6.1; 7.8] in the KBPCarb-Esubgroups to 9.6 months [95% CI, 8.4;10.8] in the KBP Cisp-E subgroup. KBP-PS_0/1 population showed better median OS, especially for the Cisp-E subgroup (10 months [95% CI, 8.7; 11.3]). CONCLUSION: In the KBP-PS_0/1 population, median OS was close to the one that was found in the IMpower133 control arm. Although this needs to be confirmed by further research, it suggests the transposability of the IMpower133 results to real-life conditions.

"Doctor, can I have less frequent injection with highly efficient treatment?" A patient centered study using an electronic choice-based conjoint analysis (ePRO) to assess real world preferences regarding erythropoiesis stimulating agent to treat anaemia in chronic kidney disease (PERCEPOLIS study).

OBJECTIVES: Patient's perception analysis appears recently in numerous studies. Conjoint analysis has been used extensively by market researchers for studying how people value the characteristics of products and services. This technique was used in a clinical study to describe perceptions and preferences of anaemic patients suffering from chronic kidney disease not on dialysis (CKDnd), regarding erythropoietin stimulating agents (ESA). METHODS: PERCEPOLIS was a French multicenter prospective non-interventional study designed to describe the relative importance of ESA attributes according to CKDnD patients. Patients fulfilled questionnaires using an electronic device (digital tablet) at baseline and after 6 months under continuous erythropoietin receptor activator (CERA) treatment. Choice-based conjoint (CBC) questionnaires were developed with multiple components: 7 ESA attributes (2 or 3 levels per attribute), 2 partial profiles per task (2 out of the 7 attributes), and 7 tasks per questionnaire. Analyses were performed according to previous ESA treatment or not. RESULTS: From 789 analyzed patients, 433 non ESA-naive patients were more than 80% to declare treatment efficacy as the most important expectative in ESA choice process (direct question) but CBC analyses revealed that frequency of injections was more crucial (relative mean weight: ∼30% versus ∼20% for efficacy). Pain at injection site and haemoglobin not exceeding the recommended target were confirmed as important criteria for patients (relative mean weights: ∼15%). No new or unexplained safety signals were noted. CONCLUSIONS: Using CBC design for the first time in a non-interventional ESA study with an electronic Patient Reported Outcome (ePRO) in an elderly population, these data showed that monthly injections and treatment efficacy were key patients' expectations relative to ESAs. CERA efficacy to maintain stable haemoglobin within the recommended range was confirmed in real-life conditions.

[Impact of comorbidities on hemoglobin stability in patients with chronic kidney insufficiency on hemodialysis, treated with CERA in current practice: The MIRIADE study]. / Impact des comorbidités sur la stabilité de l'hémoglobine chez des patients insuffisants rénaux chroniques en hémodialyse, traités par CERA en pratique courante : l'étude MIRIADE.

This national, prospective and multicenter study aimed to describe the real-life impact of comorbidities on hemoglobin stability in patients with chronic kidney disease on hemodialysis, treated with CERA in relay of an erythropoietin stimulating agent. Comorbidities were defined by the Charlson Index (adjusted on age) and hemoglobin stability as a variation of ±1g/dL after the 6-month treatment period. The 585 analyzed patients were distributed as follows according to the adjusted Charlson index: score≤3 (12% of patients), 4≤score≤5 (17%), 6≤score≤7 (31%) and score≥8 (40%). At CERA start, its median monthly dose was of 100µg for the overall population, with no changes during the treatment period and with little variation according to the comorbidity score. Patients with stable hemoglobin (56%, 67% if score≤3) were more numerous to reach the therapeutic target range between 10 and 12g/dL after 6 months (85% versus 43% if not stable hemoglobin). Patients with low C-reactive protein value (≤5mg/L ; P=0.04), no red blood cell transfusion (P=0.03), or no/low dose of intravenous iron (≤200mg ; P=0.03) were more likely to reach stable hemoglobin under CERA after 6 months. Among the 644 CERA-treated patients, 4 patients (<1%) had one serious adverse event related to treatment. A stable hemoglobin within the therapeutic target was reached in the majority of the patients after 6 months in current practice with a lower CERA dose, regardless of the comorbidities scores of patients on hemodialysis.

Tocilizumab Effectiveness After Switching from Intravenous to Subcutaneous Route in Patients with Rheumatoid Arthritis: The RoSwitch Study.

INTRODUCTION: The main objective of this work was to assess the maintenance of effectiveness of subcutaneous tocilizumab 6 months after switching from intravenous to subcutaneous formulation in patients with rheumatoid arthritis (RA) in a real-world setting. Secondary objectives aimed to describe the characteristics of patients and disease, the effectiveness at 12 months after switching, the therapeutic maintenance, and to search for predictive factors of switching. METHODS: We analyzed all the RA patients of the shared medical file "RIC Nord de France", treated with tocilizumab, switching or not from intravenous to subcutaneous tocilizumab, between April 2015 and January 2016. The primary effectiveness endpoint was the proportion of patients remaining in their DAS28-ESR category remission/low disease activity (LDA) or moving to an inferior DAS28-ESR category at 6 months. Since RoSwitch was an observational study, without randomization, a propensity score was built in a sensitivity analysis to balance on RA and patients' characteristics at inclusion between switching and no-switching groups. RESULTS: An improvement of initial DAS28-ESR category or maintenance in DAS28-ESR remission/LDA at 6 months was shown in 203 of the 285 patients with an evaluation for the primary criterion (71.2%, 95% CI [65.6-76.4%]) without differences between groups (73.3%, 95% CI [63.0-82.1%] vs. 70.3%, 95% CI [63.3-76.6%]). The RoSwitch study showed the maintenance of effectiveness at 6 and 12 months. Similar therapeutic maintenance rates were observed for switch and no-switch patients. No clinical factor was associated with the switch in patients in remission/LDA at inclusion. CONCLUSIONS: The RoSwitch study showed the maintenance of effectiveness at 6 months in RA patients switching from intravenous (IV) to subcutaneous (SC) tocilizumab. FUNDING: Roche SAS and Chugai Pharma France.

A multidisciplinary approach to oncology trials: Study conduct of the ANTHALYA trial.

Clinical trials that combine medical therapy and surgical treatment pose a number of challenges. The ANTHALYA trial investigated the efficacy and safety of adding bevacizumab to neoadjuvant carboplatin-paclitaxel chemotherapy prior to interval debulking surgery (IDS) in patients with ovarian cancer. The success of the trial depended on the efficacy and the safety of the combination and on the surgical effort. Furthermore, at the time of study design, neoadjuvant bevacizumab had not been investigated in ovarian cancer patients and it was unknown if neoadjuvant angiogenic therapy would be well tolerated or would negatively impact the success of IDS. Therefore, safety in the ANTHALYA trial was paramount. To overcome these challenges we conducted the trial in collaboration with French oncologists and surgeons who were experts in the multidisciplinary treatment of ovarian cancer. Toxicity was monitored during the neoadjuvant and IDS periods using a Bayesian approach which provided flexibility in the decision-making process regarding the continuation or rapid discontinuation of the trial in response to a safety signal. We implemented a stopping rule for safety based on a number of pre-defined bevacizumab-related complications of special interest. We also developed an electronic case report form, which greatly facilitated the collection and dissemination of safety information and other trial data. Here we describe how we used these tools to ensure the successful conduct of ANTHALYA and report how it is possible to mix a Bayesian approach for monitoring toxicity and a frequentist approach for evaluating efficacy within the same trial.

Newborn screening levels of 17-hydroxyprogesterone in very low birth weight infants and the relationship to chronic lung disease.

OBJECTIVES: 17-Hydroxyprogesterone (17-OHP), an intermediary hormone in cortisol synthesis, has been shown to be elevated in premature infants. However, the relationship between levels of 17-OHP with chronic lung disease (CLD) have not been extensively explored. The objective of this study was to determine whether there is an association between CLD and levels of 17-OHP in a population of very low birth weight infants. STUDY DESIGN: Cohort study of very low birth weight infants cared for at a single level 3 NICU during a 3-year period from July 2001-July 2004, n=435. Infants had a minimum of one screen for 17-OHP. 17-OHP was measured on the 5th day of life and at 2-4 weeks of life as part of the State of Delaware Newborn Screening Program. Statistical analysis included chi-squared, Pearson correlation, and logistic regression. RESULTS: Levels of 17-OHP were higher at the time of the 1st screen compared to the 2nd screen (42.2 +/- 36.7 vs 23.5 +/- 32.3 ng/ml, respectively, p = 0.01). After controlling for potential confounding variables, gestational age and prenatal steroids were independently associated with 17-OHP. However, logistic regression analysis showed no association between a 1 log increase in levels of 17-OHP with the outcomes of CLD (odds ratio 1.7, 95% CI 0.7-3.8), or death and/or CLD (odds ratio 2.1, 95% CI 0.9-4.8). CONCLUSIONS: In our population of very low birth weight infants elevated levels of 17-OHP were not associated with the development of CLD.