Disparities in the uptake of telemedicine and implications for clinical trial enrollment in breast cancer patients

Purpose/Objectives: Since the COVID-19 pandemic, telemedicine has become an attractive alternative to office visits in routine radiation oncology practice. The purpose of this study was to identify factors associated with patient preference for an initial consult telemedicine visit and correlation with clinical trial enrollment. Materials/Methods: We evaluated breast cancer patients seen during the open enrollment of a prospective randomized controlled non inferiority trial evaluating radiation fibrosis with five versus three fractions from 07/13/2020 to 05/13/2021. Univariate and multivariate logistic regression models were used to identify factors associated with virtual vs inperson initial consultation and enrolled vs not enrolled patients. All statistical tests were two-sided and the null hypothesis was rejected for p< 0.05. Result(s): We identified 476 patient consultations with 259 office visits and 217 telemedicine visits. On multivariate analysis, increased age, unemployment, chemotherapy receipt and radiation at NYU were associated with decreased usage of telemedicine for consultation visit. Out of 217 patients who underwent a telemedicine initial consultation, 10% were eligible to enroll on the trial and of those eligible, 76% enrolled. Out of 259 patients who underwent office visit initial consultation, 14% were eligible to enroll on the trial and of those eligible, 53% enrolled. Among eligible patients, there was no statistically significant difference in clinical trial enrollment between telemedicine and office visits. There was no statistically significant difference in patient characteristics between enrolled vs not enrolled patients. Conclusion(s): Though patient and disease characteristics remained similar between patients undergoing telemedicine and office visits consultations, increased age, unemployment and receipt of chemotherapy were associated with lower usage of telemedicine. Those who underwent in person initial consultation were also more likely to subsequently receive their radiation at our clinic. Further studies are needed to better define underlying reasons for patient selection and impact on care and trial enrollment in order to ensure equal access and benefit from telemedicine, especially in already vulnerable patient populations.

Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up.

INTRODUCTION: This study compared the pharmacokinetics (PK) of the ravulizumab on-body delivery system for subcutaneous (SUBQ) administration with intravenous (IV) ravulizumab in eculizumab-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: Patients with PNH received SUBQ ravulizumab (n = 90) or IV ravulizumab (n = 46) during the 10-week randomized treatment period; all patients then received SUBQ ravulizumab during an extension period (< 172 weeks; data cutoff 1 year). Primary endpoint was day 71 serum ravulizumab trough concentration (Ctrough). Secondary endpoints were ravulizumab Ctrough and free C5 over time. Efficacy endpoints included change in lactate dehydrogenase (LDH), breakthrough hemolysis (BTH), transfusion avoidance, stabilized hemoglobin, and Treatment Administration Satisfaction Questionnaire (TASQ) score. Safety, including adverse events (AEs) and adverse device effects (ADEs), was assessed until data cutoff. RESULTS: SUBQ ravulizumab demonstrated PK non-inferiority with IV ravulizumab (day 71 SUBQ/IV geometric least-squares means ratio 1.257 [90% confidence interval 1.160-1.361; p < 0.0001]). Through 1 year of SUBQ administration, ravulizumab Ctrough values were > 175 µg/mL (PK threshold) and free C5 < 0.5 µg/mL (PD threshold). Efficacy endpoints remained stable: mean (standard deviation, SD) LDH percentage change was 0.9% (20.5%); BTH events, 5/128 patients (3.9%); 83.6% achieved transfusion avoidance; 79.7% achieved stabilized hemoglobin. Total TASQ score showed improved satisfaction with SUBQ ravulizumab compared with IV eculizumab (mean [SD] change at SUBQ day 351, - 69.3 [80.1]). The most common AEs during SUBQ treatment (excluding ADEs) were headache (14.1%), COVID-19 (14.1%), and pyrexia (10.9%); the most common ADE unrelated to a device product issue was injection site reaction (4.7%). Although many patients had ≥ 1 device issue-related ADE, full SUBQ dose administration was achieved in 99.9% of attempts. CONCLUSIONS: SUBQ ravulizumab provides an additional treatment choice for patients with PNH. Patients may switch to SUBQ ravulizumab from IV eculizumab or ravulizumab without loss of efficacy. TRIAL REGISTRATION: NCT03748823.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by the destruction of red blood cells (hemolysis) within blood vessels. In addition to hemolysis, patients with PNH are susceptible to life-threatening blood clots (thromboses). Eculizumab and ravulizumab are types of treatments for PNH, called C5 inhibitors. In the blood, these treatments bind to C5 protein and prevent the destruction of red blood cells, reducing the symptoms and complications of PNH. Both treatments are approved for use via intravenous (through the vein) administration. Ravulizumab is also approved in the USA for use via subcutaneous (under the skin) administration. This study compared subcutaneous ravulizumab with intravenous ravulizumab in patients with PNH who had previously been treated with eculizumab. During the initial treatment period of 71 days, 90 patients received subcutaneous ravulizumab and 46 received intravenous ravulizumab. Following this period, all patients received subcutaneous ravulizumab. At day 71, the amount of ravulizumab in the blood of patients taking subcutaneous ravulizumab was no less than in patients taking intravenous ravulizumab and was maintained over 1 year of treatment. Efficacy measures (how well it works) remained stable in patients taking subcutaneous ravulizumab for 1 year and side effects were comparable with those of intravenous ravulizumab. Patients reported more satisfaction with subcutaneous ravulizumab than intravenous eculizumab, as assessed by the Treatment Administration Satisfaction Questionnaire. This study showed that patients with PNH can switch from intravenous eculizumab or ravulizumab to subcutaneous ravulizumab without loss of efficacy. Subcutaneous ravulizumab provides an additional treatment choice for patients with PNH.

Safety and immunogenicity of SII-NVX-CoV2373 (COVID-19 vaccine) in adults in a phase 2/3, observer-blind, randomised, controlled study.

Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13-22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

Efficacy Of Distance Learning For Cardiopulmonary Resuscitation Training Utilizing Smartphone App And Mannikin Delivery-collection System

Aim of the study: Effective CPR training is important for provision of high-quality bystander cardiopulmonary resuscitation (CPR). However, the COVID-19 pandemic has hindered conventional face-to-face CPR training. To overcome the limitation, we developed a distance learning CPR training course (HEROS-Remote) that utilized a smartphone app and a delivery-collection system for CPR training manikins. The objective of the study was to evaluate the efficacy of the HEROSRemote course by comparing chest compression quality between trainees who participated in the conventional CPR training (C-training) and HEROS-Remote course (R-training). Method(s): The non-inferiority trial included adult nonhealthcare providers who applied for CPR training. Both groups underwent 2-minute post-training chest compression test followed by course survey on trainees' course and delivery system satisfaction. The primary outcome of the study was mean chest compression depth during the 2-minute post-training test. Result(s): A total of 180 trainees were enrolled with 90 trainees for each training group. There was no statistically significant difference in chest compression depth between R-training and C-training groups (67.4 vs. 67.8, p=0.78) as well as proportion of adequate chest compression depth, chest compression rate, proportion of chest compressions with complete chest recoil and chest compression score (90.8 vs. 92.1, p=0.69;110.8 vs. 110.4, p=0.60;89.8 vs. 94.7, p=0.05;92.7 vs. 95.5, p=0.16, respectively). In the R-training group, 90.0% of the trainees were satisfied with the course, 96% responded that the delivery system was satisfactory and convenient. Conclusion(s): The R-training course was noninferior to the C-training course. The distance learning CPR training method utilizing smartphone app and mannikin delivery-collection system had high user satisfaction and was logistically feasible.

Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.

BACKGROUND/AIMS: The HIV Prevention Trials Network 083 trial was a group-sequential non-inferiority trial designed to compare HIV incidence under a novel experimental regimen for HIV prevention, long-acting injectable cabotegravir, with an active-control regimen of daily oral tenofovir disoproxil fumarate/emtricitabine (brand name Truvada). In March of 2020, just as the trial had completed enrollment, the COVID-19 pandemic threatened to prevent trial participants from attending study visits and obtaining study medication, motivating the study team to update the interim monitoring plan. The Data and Safety Monitoring Board subsequently stopped the trial at the first interim review due to strong early evidence of efficacy. METHODS: Here we describe some unique aspects of the trial's design, monitoring, analysis, and interpretation. We illustrate the importance of computing point estimates, confidence intervals, and p values based on the sampling distribution induced by sequential monitoring. RESULTS: Accurate analysis, decision-making and interpretation of trial results rely on pre-specification of a stopping boundary, including the scale on which the stopping rule will be implemented, the specific test statistics to be calculated, and how the boundary will be adjusted if the available information fraction at interim review is different from planned. After appropriate adjustment for the sampling distribution and overrun, the HIV Prevention Trials Network 083 trial provided strong evidence that the experimental regimen was superior to the active control. CONCLUSIONS: For the HIV Prevention Trials Network 083 trial, the difference between corrected inferential statistics and naive results was quite small-as will often be the case-nevertheless, it is appropriate to report and publish the most accurate and unbiased statistical results.

Immunogenicity and safety of an egg culture-based quadrivalent inactivated non-adjuvanted subunit influenza vaccine in subjects ≥3 years: A randomized, multicenter, double-blind, active-controlled phase III, non-inferiority trial.

Subunit influenza vaccine only formulated with surface antigen proteins has better safety profiles relative to split-virion influenza vaccine. Compared to the traditional quadrivalent split-virion influenza vaccine, a novel quadrivalent subunit influenza vaccine is urgently needed in China. We completed a phase 3, randomized, double-blind, active-controlled, non-inferiority clinical study at two sites in Henan Province, China. Eligible volunteers were split into four age cohorts (3-8 years, 9-17 years, 18-64 years, and ≥ 65 years, based on their dates of birth) and randomly assigned (1:1) to the subunit and the split-virion ecNAIIV4 groups. All volunteers were intramuscularly administered a single vaccine dose at baseline, and children aged 3-8 years received a boosting dose at day 28. And the immune response was evaluated by measuring hemagglutinin-inhibition antibody titers against the four vaccine strains in blood samples. Safety profiles had nonsignificant differences between the study groups in ≥ 3 years cohort. Most adverse reactions post-vaccination, both local and systemic, were mild to moderate and resolved within 3 days. And no serious adverse events occurred. The immunogenicity of the trial vaccine was non-inferior to the comparator. Further, a two-dose vaccine series can provide better seroprotection than that of a one-dose series in children aged 3-8 years, with clinically acceptable safety profiles. Clinical Trials Registration. ChiCTR2100049934.

Innovative Tele-Instruction Approach Impacts Basic Life Support Performance: A Non-inferiority Trial.

Background: Sustaining Basic Life Support (BLS) training during the COVID-19 pandemic bears substantial challenges. The limited availability of highly qualified instructors and tight economic conditions complicates the delivery of these life-saving trainings. Consequently, innovative and resource-efficient approaches are needed to minimize or eliminate contagion while maintaining high training standards and managing learner anxiety related to infection risk. Methods: In a non-inferiority trial 346 first-year medical, dentistry, and physiotherapy students underwent BLS training at AIXTRA-Competence Center for Training and Patient Safety at the University Hospital RWTH Aachen. Our objectives were (1) to examine whether peer feedback BLS training supported by tele-instructors matches the learning performance of standard instructor-guided BLS training for laypersons; and (2) to minimize infection risk during BLS training. Therefore, in a parallel group design, we compared arm (1) Standard Instructor Feedback (SIF) BLS training (Historical control group of 2019) with arm (2) a Tele-Instructor Supported Peer-Feedback (TPF) BLS training (Intervention group of 2020). Both study arms were based on Peyton's 4-step approach. Before and after each training session, objective data for BLS performance (compression depth and rate) were recorded using a resuscitation manikin. We also assessed overall BLS performance via standardized instructor evaluation and student self-reports of confidence via questionnaire. Non-inferiority margins for the outcome parameters and sample size calculation were based on previous studies with SIF. Two-sided 95% confidence intervals were employed to determine significance of non-inferiority. Results: The results confirmed non-inferiority of TPF to SIF for all tested outcome parameters. A follow-up after 2 weeks found no confirmed COVID-19 infections among the participants. Conclusion: Tele-instructor supported peer feedback is a powerful alternative to in-person instructor feedback on BLS skills during a pandemic, where infection risk needs to be minimized while maximizing the quality of BLS skill learning. Trial registration: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00025199, Trial ID: DRKS00025199.

IMPACT OF POSTOPERATIVE TELEMEDICINE VISIT VS. IN-PERSON VISIT ON PATIENT SATISFACTION DURING THE COVID-19 PANDEMIC: A RANDOMIZED CLINICAL TRIAL

Purpose/Background: Although telemedicine utilization has increased dramatically during the COVID-19 pandemic, the impact of telemedicine vs. in-person postoperative visits on patient satisfaction has not been studied. Hypothesis/Aim: We hypothesized that telemedicine visits would be non-inferior to in-person visits in terms of postoperative colorectal surgery patient satisfaction. Methods/Interventions: We conducted a randomized non-inferiority trial from September 2020 to February 2021 comparing postoperative telemedicine visit (Arm T) or in-person clinic visit (Arm I) after trans-abdominal colorectal surgery. Key inclusion criteria were patients age ≥ 18 undergoing trans-abdominal colorectal surgery and patients with a computer and/ or mobile phone with both audio and video capabilities. Patients who required planned physical intervention during their first postoperative visit (e.g. drain removal) and patients undergoing trans-anal or anorectal procedures only were excluded. Patients in the experimental group (Arm T) received their first postoperative visit via telemedicine. Patients in the control group (Arm I) received their first postoperative visit in person. All participants were asked to complete a seven-item patient satisfaction survey electronically within 24 hours after each postoperative visit, which was scored out of a total of 35. The primary endpoint was total patient satisfaction score. Secondary endpoints included patient-reported safety, length of visit, willingness of patients to recommend the practice to their peers, 60-day rate of readmission, and 60-day rate of re-operation. Results/Outcome(s): A total of 46 patients were analyzed with 23 each in Arm T and Arm I. The mean age of our study cohort was 50.6 (SD 17.7) years and 52% were female. No significant differences were found between groups in terms of baseline characteristics. With respect to the primary endpoint of total satisfaction score out of 35, mean difference in total scores between patients in Arm T vs. patients in Arm I was -0.6 (97.5% CI -1.7 - ∞), excluding the non-inferiority limit Δ of -2, demonstrating that patient satisfaction scores in Arm T were non-inferior to those in Arm I. There were no significant differences between groups in terms of secondary endpoints. Limitations: Patients who did not have a computer or mobile device with both video and audio capabilities were excluded, which may have introduced selection bias. The conduction of our trial during the COVID-19 pandemic may have influenced patient desire to participate in telemedicine in order to maintain social distancing, which may have resulted in a more expeditious recruitment process compared to non-pandemic times. Conclusions/Discussion: Postoperative telemedicine visits were a safe and time-efficient option that maintained high patient satisfaction compared to in-person postoperative visits during the COVID-19 pandemic. (Table Presented).

A randomized, pragmatic trial investigating the timing of radiotherapy and endocrine in patients with early stage breast cancer (REaCT-RETT trial)

The optimal timing of commencing adjuvant endocrine therapy (ET) relative to adjuvant radiotherapy (RT) (i.e. concurrent with or sequential to radiotherapy) remains unknown. A systematic review performed by our team was unable to answer this question due to a lack of high quality, randomized data on concurrent versus sequential ET and RT. Surveys of physicians confirmed this uncertainty and highlighted theoretical concerns for increased side effects with concurrent treatment. Respondents showed keen interest in obtaining real world, randomized data to guide clinical practice. REaCT-RETT is a pragmatic, randomized, non-inferiority trial comparing concurrent and sequential ET and RT in early breast cancer (EBC). The primary endpoint will assess the change in ET side effects at baseline and 3 months post radiation, using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), with primary analysis based on an analysis of covariance (ANCOVA). With a sample size of 176 patients (88 per arm), an ANCOVA would have 80% power (α=0.05) to detect effect sizes as small as 0.25 regardless of the correlation with covariates. It is hypothesized that concurrent therapy will be non-inferior to sequential therapy in terms of ET side effects. Secondary endpoints will examine RT toxicity, ET compliance, quality of S life, and cost-effectiveness. Patients with HR positive EBC planned to receive both adjuvant ET and RT were eligible. Patients who previously received ET for invasive breast cancer, or RT in the same breast, were excluded. The trial is conducted by The Ottawa Hospital's (TOH) innovative Rethinking Clinical Trials (REaCT) program (https://react.ohri.ca/) which strives to improve access to patient-centered, pragmatic clinical trials by removing barriers for patients and researchers. Integral features of the program include broad eligibility criteria, a verbal consent model, and pragmatic data collection and assessment procedures. REaCT is the largest pragmatic cancer clinical trials program in Canada, with over 3, 200 patients randomized in 18 clinical trials at 15 sites across Canada. REaCT-RETT accrued patients from September 2019 to January 2021. Data collection is ongoing, with final patient follow up expected April 2022. The timing of accrual provided a unique opportunity to adapt in response to restrictions due to the COVID-19 pandemic, which began to impact trial sites in March 2020. The target sample size was met with 262 patients randomized (1:1) across 3 sites in Ontario, 98% from TOH. A mean of 19 patients/month were accrued prior to the pandemic, compared to a mean of 13 patients/month after March 2020. Twenty-two patients were removed due to withdrawal of consent, ineligibility, or physician choice, and the pandemic was not a significant contributing factor. Since March 2020 there have been 772 patient follow ups, of which 47% (364/772) have been virtual. Only 10% (102/1028) of trial mandated appointments have been missed to date. Compliance with baseline and 3-month FACT-ES questionnaires for the primary endpoint in evaluable patients was 90% (215/240) and 83% (198/240), respectively. The pandemic posed several challenges to the REaCT-RETT study including a decline in patient accrual, poor accrual at peripheral sites due to delayed opening, and a rapid switch to virtual patient care. However, the nimble REaCT methodology enabled virtual patient consent and data collection during the pandemic, allowing the trial to continue successfully, with final data expected for presentation summer 2022. Finally, despite the challenges of COVID-19 we have seen that patients and physicians remain interested in research, and we are applying valuable lessons learned to forthcoming REaCT trials to strengthen their performance during and beyond the ongoing pandemic.

Current issues in the design and analysis of COVID-19 vaccine efficacy trials

The global COVID-19 pandemic has posed unprecedented challenges to public health, not to mention the global economy and way of life. The pace of vaccine development has been unprecedented and major successes have been realized, with three vaccines having received authorization for use in several countries around the globe following efficacy trials demonstrating high efficacy at preventing COVID-19 disease. However, considerable challenges remain. The immunological predictors of and mechanisms for the efficacy have yet to be defined, and identifying such immune correlates will be critical for bridging the efficacy to populations not included in the original efficacy trials. Additional vaccines also require evaluation to meet global demand. And evaluating the effects of vaccines on onward transmission of infection is imperative to guide policy and optimize vaccine uptake. The talks in this session will pertain to these topics of discovering immunological correlates, designing non-inferiority studies of new candidate COVID-19 vaccines, bridging efficacy of efficacious vaccines to new populations, and designing studies of vaccine efficacy against transmission. This session will include presentations by both academic and industry partners in the field of COVID-19 vaccine development. As leaders in the field, the speakers will articulate the scientific and statistical challenges faced for a given problem, and articulate and illustrate the practical solutions based on ongoing and planned studies. The session chair will work with speakers to ensure that the talks are appropriately sequenced and complementary. Each talk will be 17 min long, followed by 3 min for question and answer, with 10 min discussion at the end of the session. Given the rapid pace with which the COVID-19 field is moving, the topics will be re-evaluated in coming months to ensure that they are relevant and timely. The development and deployment of effective COVID-19 vaccines is currently among the highest public health priorities. The general topics for the talks (immunological correlates of vaccine protection;noninferiority trial design;bridging studies;and transmission studies), are applicable to multiple pathogens, and the statistical problems encountered have features common to clinical trials in other fields.

A Counseling Application as an Alternative Tool in Increasing Coping Self-Efficacy Among University Students With Academic Distress During Coronavirus Disease 2019 Pandemic in Indonesia: A Study Protocol for a Randomized Controlled Non-Inferiority Trial.

The coronavirus disease 2019 (COVID-19) pandemic increased education-related distress among University students globally, including in Indonesia. Psychological factors, such as academic demands, limited opportunity to meet their peers, problematic use of technology, and domestic problems, influenced the well-being of the students, leading to poor academic performance. A mobile-based counseling application was developed to address the distress among University students. The application was meant to reach students living remotely to enable them to access psychological assistance. Therefore, the purpose of this study was to describe a protocol aimed to evaluate the equivalence of the application when compared to the Treatment-As-Usual (TAU) in increasing the coping self-efficacy (CSE) and resilience of students as well as in decreasing their level of depression. A two-armed parallel randomized control non-inferiority trial will be conducted among approximately 430 students with selected academic problems. The participants will be randomly allocated into the TAU and the intervention groups. The primary and secondary outcomes will be measured by the Indonesian versions of the Coping Self-Efficacy (CSE) Scale, the Resilience Scale (RS-14), and the Patient Health Questionnaire (PHQ-9). The data will be collected at baseline, at the end of each session, and after 3 months. The outcomes will be analyzed using repeated-measures ANOVAs, intention-to-treat, and per-protocol analysis. If proven, the application will be used as an alternative media in helping the students. Clinical Trial Registration: Thailand Clinical Trials Registry (TCTR20200530001); Date of registration: May 28, 2020.

Partial oral antibiotic treatment for bacterial brain abscess: an open-label randomized non-inferiority trial (ORAL).

BACKGROUND: The advised standard treatment for bacterial brain abscess following surgery is 6 to 8 weeks of intravenous (IV) antibiotic treatment, but an early switch to oral antibiotic treatment has been suggested to be equally effective. METHODS: This investigator-initiated, international, multi-center, parallel group, open-label, randomized (1:1 allocation) controlled trial will examine if oral treatment after 2 weeks of IV antibiotic therapy is non-inferior to standard 6-8 weeks of IV antibiotics for bacterial brain abscess in adults (≥ 18 years of age). The study will be conducted at hospitals across Denmark, the Netherlands, France, Australia, and Sweden. Exclusion criteria are severe immunocompromise or impaired gastro-intestinal absorption, pregnancy, device-related brain abscesses, and brain abscess caused by nocardia, tuberculosis, or Pseudomonas spp. The primary objective is a composite endpoint at 6 months after randomization consisting of all-cause mortality, intraventricular rupture of brain abscess, unplanned re-aspiration or excision of brain abscess, relapse, or recurrence. The primary endpoint will be adjudicated by an independent blinded endpoint committee. Secondary outcomes include extended Glasgow Outcome Scale scores and all-cause mortality at end of treatment as well as 3, 6, and 12 months since randomization, completion of assigned treatment, IV catheter associated complications, durations of admission and antibiotic treatment, severe adverse events, quality of life scores, and cognitive evaluations. The planned sample size is 450 patients for a one-sided alpha of 0.025 and a power of 90% to exclude a difference in favor of standard treatment of more than 10%. Date of initiation of first study center was November 3, 2020, with active recruitment for 3 years and follow-up for 1 year of all patients. DISCUSSION: The results of this study may guide future recommendations for treatment of bacterial brain abscess. If early transition to oral antibiotics proves non-inferior to standard IV treatment, this will provide considerable health and costs benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT04140903, first registered 28.10.2019. EudraCT number: 2019-002845-39, first registered 03.07.2019.

Teaching Cognitive Behavior Therapy to Postgraduate Health Care Professionals in Times of COVID 19 - An Asynchronous Blended Learning Environment Proved to Be Non-inferior to In-Person Training.

Training of postgraduate health professionals on their way to becoming licensed therapists for Cognitive Behavior Therapy (CBT) came to a halt in Germany in March 2020 when social distancing regulations came into effect. Since the German healthcare system almost exclusively relies on this profession when it comes to the implementation of CBT and 80% of those therapists active in 2010 will have retired at the end of 2030, it is critical to assess whether online CBT training is as satisfactory as classroom on-site CBT training. An asynchronous, blended, inverted-classroom online learning environment for CBT training (CBT for psychosis) was developed as an emergency solution. It consisted of pre-recorded CBT video lectures, exercises to train interventions in online role-plays, and regular web conferences. Training was provided at five different training institutes in Germany (duration 8-16 h). Postgraduate health care professionals (psychiatrists and psychologists) (n = 43) who received the online CBT training filled out standard self-report evaluations that assessed satisfaction and didactic quality. These evaluations were compared to those evaluations of students (n = 142) who had received in-person CBT training with identical content offered by the same CBT trainer at the same training institutes before the COVID-19 crisis. Both groups were comparable with respect to interest in the subject and prior knowledge. We tested non-inferiority hypotheses using Wilcoxon-Mann-Whitney ROC-curve analyses with an equivalence margin corresponding to a small-to-medium effect size (d = 0.35). The online training evaluations were non-inferior concerning information content, conception of content, didactic presentation, assessment of the trainer as a suitable role-model, working atmosphere, own commitment, and practical relevance. In contrast, we could not exclude a small effect in favor of in-person training in professional benefit and room for active participation. Our results suggest that delivering substantial CBT knowledge online to postgraduate health-professionals is sufficient, and at most incurs minimal loss to the learning experience. These encouraging findings indicate that integrating online elements in CBT teaching is an acceptable option even beyond social distancing requirements.

COVID-19 vaccine trials: The potential for "hybrid" analyses.

BACKGROUND: Although several COVID-19 vaccines have been found to be effective in rigorous evaluation and have emerging availability in parts of the world, their supply will be inadequate to meet international needs for a considerable period of time. There also will be continued interest in vaccines that are more effective or have improved scalability to facilitate mass vaccination campaigns. Ongoing clinical testing of new vaccines also will be needed as variant strains continue to emerge that may elude some aspects of immunity induced by current vaccines. Randomized clinical trials meaningfully enhance the efficiency and reliability of such clinical testing. In clinical settings with limited or no access to known effective vaccines, placebo-controlled randomized trials of new vaccines remain a preferred approach to maximize the reliability, efficiency and interpretability of results. When emerging availability of licensed vaccines makes it no longer possible to use a placebo control, randomized active comparator non-inferiority trials may enable reliable insights. METHODS: In this article, "hybrid" methods are proposed to address settings where, during the conduct of a placebo-controlled trial, a judgment is made to replace the placebo arm by a licensed COVID-19 vaccine due to emerging availability of effective vaccines in regions participating in that trial. These hybrid methods are based on proposed statistics that aggregate evidence to formally test as well as to estimate the efficacy of the experimental vaccine, by combining placebo-controlled data during the first period of trial conduct with active-controlled data during the second period. RESULTS: Application of the proposed methods is illustrated in two important scenarios where the active control vaccine would become available in regions engaging in the experimental vaccine's placebo-controlled trial: in the first, the active comparator's vaccine efficacy would have been established to be 50%-70% for the 4- to 6-month duration of follow-up of its placebo-controlled trial; in the second, the active comparator's vaccine efficacy would have been established to be 90%-95% during that duration. These two scenarios approximate what has been seen with adenovirus vaccines or mRNA vaccines, respectively, assuming the early estimates of vaccine efficacy for those vaccines would hold over longer-term follow-up. CONCLUSION: The proposed hybrid methods could readily play an important role in the near future in the design, conduct and analysis of randomized clinical trials performed to address the need for multiple additional vaccines reliably established to be safe and have worthwhile efficacy in reducing the risk of symptomatic disease from SARS-CoV-2 infections.

COVID-19 vaccine trials: The use of active controls and non-inferiority studies.

BACKGROUND: Recently emerging results from a few placebo-controlled randomized trials of COVID-19 vaccines revealed estimates of 62%-95% relative reductions in risk of virologically confirmed symptomatic COVID-19 disease, over approximately 2-month average follow-up period. Additional safe and effective COVID-19 vaccines are needed in a timely manner to adequately address the pandemic on an international scale. Such safe and effective vaccines would be especially appealing for international deployment if they also have favorable stability, supply, and potential for implementation in mass vaccination campaigns. Randomized trials provide particularly reliable insights about vaccine efficacy and safety. While enhanced efficiency and interpretability can be obtained from placebo-controlled trials, in settings where their conduct is no longer possible, randomized non-inferiority trials may enable obtaining reliable evaluations of experimental vaccines through direct comparison with active comparator vaccines established to have worthwhile efficacy. METHODS: The usual objective of non-inferiority trials is to reliably assess whether the efficacy of an experimental vaccine is not unacceptably worse than that of an active control vaccine previously established to be effective, likely in a placebo-controlled trial. This is formally achieved by ruling out a non-inferiority margin identified to be the minimum threshold for what would constitute an unacceptable loss of efficacy. This article not only investigates non-inferiority margins, denoted by δ, that address the usual objective of determining whether the experimental vaccine is "at least similarly effective to" the active comparator vaccine in the non-inferiority trial, but also develops non-inferiority margins, denoted by δo, intended to address the worldwide need for multiple safe and effective vaccines by satisfying the less stringent requirement that the experimental vaccine be "at least similarly effective to" an active comparator vaccine having efficacy that satisfies the widely accepted World Health Organization-Food and Drug Administration criteria for "worthwhile" vaccine efficacy. RESULTS: Using the margin δ enables non-inferiority trials to reliably evaluate experimental vaccines that truly are similarly effective to an active comparator vaccine having any level of "worthwhile" efficacy. When active comparator vaccines have efficacy in the range of 50%-70%, non-inferiority trials designed to use the margin δo have appealing properties, especially for experimental vaccines having true efficacy of approximately 60%. CONCLUSION: Non-inferiority trials using the proposed margins may enable reliable randomized evaluations of efficacy and safety of experimental COVID-19 vaccines. Such trials often require approximately two- to three-fold the person-years follow-up than a placebo-controlled trial. This could be achieved, without substantive increases in sample size, by increasing the average duration of follow-up from 2 months to approximately 4-6 months, assuming efficacy of the active comparator vaccine has been reliably evaluated over that longer duration.