National Institutional Review Board Research Articles

P688 Comparative Effectiveness of Ustekinumab Versus Vedolizumab in Treating Crohn’s Disease After Failure of Anti-TNF Agents: Real-World Evidence

Abstract Background Despite effective anti-TNF agents in treating Crohn’s disease (CD), some recipients experience primary or secondary non-responses, requiring alternative options. Ustekinumab and vedolizumab have not been compared in randomized controlled trials (RCTs) among CD population. Thus, we used real-world data to compare ustekinumab and vedolizumab at 12 weeks after failure of TNF inhibitors. Methods A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia. Patients with CD who had not responded to anti-TNF agents and had never been exposed to vedolizumab and/or ustekinumab were included. Children ≤ 18 years of age, naïve CD patients, CD patients using only anti-TNF agents, and patients who lost follow up were excluded. Primary endpoints were clinical improvements, which were measured by Harvey-Bradshaw Index scores at 12 weeks, and clinical remission, which was measured as an ordinal outcome. Remission clinically, biochemically, and endoscopically; clinical response; cumulative steroid dose; and corticosteroid-free days were secondary endpoints. Using probabilistic Bayesian models and proportional odds models, we analyzed outcomes, and the posterior distribution was used to calculate the probability of treatment effectiveness. A national institutional review board approved the study. Results Five hundred forty-six patients received biological agents for inflammatory bowel disease, of whom 101 received biological agents for CD; 71 patients received ustekinumab, and 30 patients received vedolizumab. The baseline characteristics were similar except for perianal disease, which was frequently reported in ustekinumab arm (P = 0.006). Most of the patients were male (54.5%), with a median age of 32 (IQR: 26.0-38.0). Most patients (51.5%) had stricturing disease in the Ileocolonic site (70.3%). For ustekinumab, the median HBI score was 5 (IQR: 3.0 -8.0) whereas for vedolizumab, it was 5 (IQR: 4.0 -7.0). In table 1, a Bayesian multivariable proportional odds model revealed a 40% reduction in median HBI scores at 12 weeks favoring ustekinumab, with an aOR of 0.60 (95% CI: 0.25 to 1.31) and a probability of effectiveness of 75% for ustekinumab. At 12 weeks, the ordinal outcome scale was 39% lower for ustekinumab arm, with an aOR of 0.61 (95% CI: 0.26 to 1.35) and a probability of effectiveness of 73% for ustekinumab arm. Secondary endpoints showed favorable results for ustekinumab reaching up to a 90% probability of effectiveness. Conclusion Among CD patients who failed anti-TNF therapies, ustekinumab was more effective than vedolizumab. To validate these results and determine these treatments’ relative efficacy in managing CD, further investigations, including prospective studies and RCTs, are essential.

ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden—a phase III randomised double-blinded placebo-controlled study

BackgroundGonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical...

Characterization of the Viral Reservoirs Among HIV-1 Non-B Vertically Infected Adolescents Receiving Antiretroviral Therapy: Protocol for an Observational and Comparative Study in Cameroon.

Antiretroviral therapy (ART) can bring HIV-1 levels in blood plasma to the undetectable level and allow a near-normal life expectancy for HIV-infected individuals. Unfortunately, ART is not curative and must be taken for life, because within a few weeks of treatment cessation, HIV viremia rebounds in most patients except for rare elite or posttreatment controllers of viremia. The primary source of this rebound is the highly stable reservoir of latent yet replication-competent HIV-1 proviruses integrated into the genomic DNA of the resting memory cluster of differentiation 4 (CD4+) T cells. To achieve a cure for HIV, understanding the cell reservoir environment is of paramount importance. The size and nature of the viral reservoir might vary according to the timing of therapy, therapeutic response, ART duration, and immune response. The mechanisms of reservoir maintenance generally depend on the levels/type of immune recognition; in addition, the dynamics of viral persistence are different between pediatric and adult populations. This difference could become more evident as children grow toward adolescence. We aim to characterize the HIV reservoirs and their variability as per the virological and immunological profiles of HIV-1 non-B vertically infected adolescents receiving ART in Cameroon during the Adolescents' Viral Reservoirs study to provide accurate and reliable data for HIV cure research. This study will involve HIV-1 non-B vertically infected adolescents selected from an existing cohort in our institution. Blood samples will be collected for analyzing immunological/virological profiles, including CD4/CD8 count, plasma viral load, immune activation/inflammatory markers, genotyping, and quantification of HIV-1 viral reservoirs. We will equally recruit an age-matched group of HIV-negative adolescents as control for immunological profiling. This study received funding in November 2021 and was approved by the national institutional review board in December 2021. Sample collection will start in November 2022, and the study will last for 18 months. The HIV-1 sequences generated will provide information on the circulating HIV-1 subtypes to guide the selection of the most appropriate ART for the participants. The levels of immune biomarkers will help determine the immune profile and help identify factors driving persistent immune activation/inflammation in HIV-infected adolescents compared to those in HIV-uninfected adolescents. Analysis of the virological and immunological parameters in addition to the HIV-1 reservoir size will shed light on the characteristics of the viral reservoir in adolescents with HIV-1 non-B infection. Our findings will help in advancing the knowledge on HIV reservoirs, in terms of size and genetic variability in adolescents living with HIV. Such evidence will also help in understanding the effects of ART timing and duration on the size of the reservoirs among adolescents living with HIV-a unique population from whom the findings generated will largely contribute to designing functional cure strategies. PRR1-10.2196/41473.

NET-RMDs study: networks of fatigue and pain in rheumatic and musculoskeletal diseases – protocol for an international cross-sectional study

IntroductionFatigue and pain are the main symptoms of rheumatic and musculoskeletal diseases (RMDs). Healthcare professionals have a primary role in helping patients to manage both these symptoms, which are part...

Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial

IntroductionLong COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, postexertional...

Strengthening capacity in hospitals to reduce perinatal morbidity and mortality through a codesigned intervention package: protocol for a realist evaluation as part of a stepped-wedge trial of the Action Leveraging Evidence to Reduce perinatal morTality and morbidity (ALERT) in sub-Saharan Africa project

IntroductionDespite a strong evidence base for developing interventions to reduce child mortality and morbidity related to pregnancy and delivery, major knowledge–implementation gaps remain. The Action Leveraging Evidence to Reduce perinatal...

UPSHOTS IN ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA: ANALYSIS OF T-CELL BRAZIL PROJECT

T-cell Brazil Project was designed as an ambispective data collection from January 2015 to December 2022 of previously untreated patients diagnosed with Peripheral T-cell lymphoma (PTCL) or NK/T-cell lymphoma according to the revised WHO 2017 classification in Brazil. The primary and secondary end points were 2-year overall survival (OS) and progression-free survival (PFS). Clinical, treatment and survival data were also correlated. Twenty centers got approved for the study from the local and national institutional review board and registered their cases only online. OS was calculated from diagnosis date until last seen or death date, whereas PFS until first event, progression / relapse, date of death or last seen. Kaplan-Meier method was applied and a Log-rank test to compare their curves. P-value less than 5% was considered. From a total of 416 patients with PTCL, 46 (11%) were diagnosed as AITL. The median age was 65 years (31-82), with 63% males, 94% had advanced-stage disease. All patients received 61% CHOEP, 28% CHOP and 11% CT without anthracycline. 20% of pts were consolidated with autologous transplant (HSCT). There were 19 (41%) deaths, 10 by lymphoma, 8 infections, 1 new neoplasia. With 8-mo median f/u (1-36), OS at 24-mo was 27% and 2-year PFS was 21%. As consolidation, OS was 71% HSCT group vs. 16% no HSCT (P= 0.06) and PFS was 71% vs. 8%, respectively (P= 0.01). These analyses are preliminaries but show a poor outcome of AITL in our population. Most patients were treated with anthracycline-containing combination chemotherapy and just 20% received autologous HSCT. A dismal survival was shown for those who did not receive HSCT.

Nitazoxanide <i>In Vitro</i> Efficacy Against SARS CoV-2 and <i> In Vivo</i> Superiority to Placebo to Treat Moderate COVID-19 – A Phase 2 Randomized Double-Blind Clinical Trial

Background: The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates’ drugs. Nitazoxanide (NTZ) has a broad antiviral effect.Methods: The in vitro effect of NTZ in VERO E6 cells was evaluated, followed by a randomized double-blind phase two clinical trial comparing NTZ 600 mg BID versus placebo for 7 days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency. Clinical and virologic end-points and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used.Results: The in vitro inhibition of SARS-CoV-2 infection was 90% with 0.5 µM, with no cytotoxicity. Two patients died in the NTZ arm compared to 6 in the placebo arm (p=NS). NTZ was superior to placebo when considering SSD (pConclusions: The superiority of NTZ as compared to placebo in clinical and virologic outcomes, as wells as improvement of inflammatory outcomes, warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms.Trial Registration: This study was registered at ClinicalTrials.gov (NCT04348409).Funding Statement: This clinical trial was funded by FQM Farma.Declaration of Interests: AL has received grants and personal fees from Janssen Pharmaceutical;has received personal fees from Daiichi Sankyo, Cristalia Produtos Quımicos e Farmaceuticos, Libbs, Pfizer, Myralis Farma, Ache Laboratorios, Hypera Pharma, and Sanofi-Aventis; and has received grants from FQM Farma, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Biophytis, and Forum Pharmaceutical. All other authors have nothing to declare. Ethics Approval Statement: This trial was approved by the Brazilian National Institutional Review Board (CONEP; approval # CAAE- 30628420.0.0000.5412) and each local Institutional Review Boards. Informed consent has been obtained.

Creating a National IRB Preparedness Training Program for the Review of Disaster-Related Research

Disasters, both natural and manmade, are becoming more common and challenge national and global resiliency and response efforts. As a result, many government agencies have an increased interest in disaster research to strengthen preparedness, response, and recovery. With the field of disaster research greatly expanding, Institutional Review Boards (IRBs) are now being asked to review research protocols aimed at assessing health risks, exposures and outcomes from disaster survivors; however, few IRBs have significant experience reviewing disaster research protocols. As the national leaders of disaster research, the National Institutes of Health (NIH) Public Health Emergency and Disaster Research Response (DR2) Program recognized the need to develop IRB disaster-related research training curricula and protocol review tools. Key components of the DR2 program include the creation of a pre-approved disaster research protocol (Rapid Acquisition of Pre- and Post-Incident Disaster Data) and the development of the National Institute of Environmental Health Sciences (NIEHS) Working Group for Special IRB Considerations in the Review of Disaster Related Research, which established the first national recommendations that informed this innovative training program. This training program includes instructor led case studies that walk trainees through using the NIEHS Disaster Research protocol Review checklist, developing IRB Continuity of Operations Plans (I-COOP), and use of the Post-Disaster Researcher Engagement Assessment and Community Template (PD-REACT) that provides a community vulnerability assessment and disaster related contextual considerations for IRB review. These materials have been field tested and developed through mock IRB and training sessions held at the Centers for Disease Control’s (CDC) National Institute for Occupational Safety and Health (NIOSH), University of Arizona, and NIEHS. This training assesses organizations’ disaster research needs, aims to improve IRB preparedness and processes for reviewing disaster-related research and enhances institutional knowledge of best practices for disaster researchers to protect the rights and welfare of study participants. Keywords: Institutional Review Board Ethics Training Best Practices

Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients

BackgroundAcute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients.MethodsTRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals.DiscussionIf early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients.Trial registrationClinicalTrials.gov, NCT03368092. Registered on 11 December 2017.

The SMART IRB platform: A national resource for IRB review for multisite studies.

Single institutional review board (IRB) review of multisite research increased in frequency over a decade ago with a proliferation of master IRB reliance agreements supporting statewide and regional consortia and disease- and population-specific networks. Although successful, the increasing number of agreements presented significant challenges and illuminated potential benefits of a single, nationwide agreement. Anticipated changes in federal regulations highlighted the need to systematize and simplify IRB reliance. To address these challenges, the NIH National Center for Advancing Translational Sciences funded a project to establish a national IRB reliance network that would support national adoption of single IRB (sIRB) review. The Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB Platform launched in July 2016 to facilitate dissemination, adoption, and implementation of a collaboratively developed master IRB reliance agreement and supportive tools and resources. More than 580 institutions have joined SMART IRB's Master Common Reciprocal Institutional Review Board Authorization Agreement and begun using the SMART IRB platform to support sIRB arrangements. Here, we describe the tenets of the agreement and operational benefits and challenges of its use. SMART IRB's early success affirms the utility of collaborative, flexible, and centralized approaches to supporting sIRB review while highlighting the need for further national harmonization.

The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD.

P4‐255: Developing a National Institutional Review Board for Neurodegenerative Diseases

P4‐255: Developing a National Institutional Review Board for Neurodegenerative Diseases

P1‐099: Developing a national institutional review board for neurodegenerative diseases

P1‐099: Developing a national institutional review board for neurodegenerative diseases

Medical Disaster Preparedness Can't Be One-Time Exercise

Medical Disaster Preparedness Can't Be One-Time Exercise

Enhancing the routine health information system in rural southern Tanzania: successes, challenges and lessons learned

To describe and evaluate the use of handheld computers for the management of Health Management Information System data. Electronic data capture took place in 11 sentinel health centres in rural southern Tanzania. Information from children attending the outpatient department (OPD) and the Expanded Program on Immunization vaccination clinic was captured by trained local school-leavers, supported by monthly supervision visits. Clinical data included malaria blood slides and haemoglobin colour scale results. Quality of captured data was assessed using double data entry. Malaria blood slide results from health centre laboratories were compared to those from the study's quality control laboratory. The system took 5 months to implement, and few staffings or logistical problems were encountered. Over the following 12 months (April 2006-March 2007), 7056 attendances were recorded in 9880 infants aged 2-11 months, 50% with clinical malaria. Monthly supervision visits highlighted incomplete recording of information between OPD and laboratory records, where on average 40% of laboratory visits were missing the record of their corresponding OPD visit. Quality of microscopy from health facility laboratories was lower overall than that from the quality assurance laboratory. Electronic capture of HMIS data was rapidly and successfully implemented in this resource-poor setting. Electronic capture alone did not resolve issues of data completeness, accuracy and reliability, which are essential for management, monitoring and evaluation; suggestions to monitor and improve data quality are made.

Commentary on “Developing a national strategy to prevent dementia: Leon Thal Symposium 2009.” The rationale for a National Institutional Review Board for neurodegenerative diseases

The published proceedings of the second Annual Leon Thal Symposium (Alzheimers Dement 2009;5:85–92) have added to the open discussion among leaders in this field, with respect to the development of a national strategy for accelerating the discovery of preventative interventions for Alzheimer's disease. One of the recommended “action steps” detailed in that report centers on the establishment of a National Institutional Review Board for neurodegenerative diseases. The purpose of this new ethical oversight panel would be to increase the efficiency with which large-scale multi-site trials are conducted. This essay expands on this recommendation, and two potential organizational models are briefly considered. A well-designed, highly-qualified, and responsive National Institutional Review Board for neurodegenerative diseases would serve the direct interest of protecting the rights, welfare, and safety of our older citizens, who so generously contribute their time, energy, and comfort to advance research to discover new treatments for this devastating disease.

Ex vivo MRI of axillary lymph nodes in breast cancer

Purpose To provide a strategy for precise co-localization of lymph nodes on axillary lymph-node dissection (ALND) specimens both on pathology and MR. To identify nodal features suggestive of metastatic involvement on a node-to-node basis. Materials and methods National Institutional review-board approved this prospective study of 18 patients with breast cancer referred for ALND. Ex vivo T1 and inversion recovery (IR) T2 WI of ALND specimens tightly positioned within scaled plastic cranes was performed immediately after surgery. The correspondence of MR-based or pathologically based nodes location was assessed. The MR size and morphological presentation of metastatic and normal nodes were compared (Student's t-test or Mann–Whitney test). Quantitative variables were compared using Pearson coefficient. Results 207 nodes were retrieved on pathology and 165 on MR. MR–pathological correlation of nodes location was high regarding MR-identified nodes ( r = 0.755). An MR short axis threshold of 4 mm yielded the best predictive value for metastatic nodal involvement (Se = 78.6%; Sp = 62.3%). Irregular contours (Se = 35.7%; Sp = 96.7%), central nodal hyper-intensity on IR T2 WI (Se = 57.1%; Sp = 91.4%), and a cortical thickness above 3 mm (Se = 63.6%; Sp = 83.2%) were significantly associated with metastatic involvement. Conclusion Ex vivo MR allows node-to-node correlation with pathology. Morphological MR criteria can suggest metastatic involvement.

Social and Behavioral Researchers' Experiences With Their IRBs

A national survey on researchers' experiences with their institutional review boards (IRBs) is presented, focused exclusively on social and behavioral researchers. A wide range of experiences is apparent in the data, especially in terms of turnaround time for submitted protocols, incidence of data collection without prior IRB approval, and stated reasons for “going solo.” Sixty-two percent felt that the turnaround time they typically experience is “reasonable,” and 44% said they had not experienced long delays in obtaining approval. However, 48% of respondents reported either conducting a project without IRB approval or modifying an existing project without IRB approval, with anticipated time for approval being the dominant reason offered for doing so. This adds a new dimension to the widely discussed “national IRB crisis” (e.g., Illinois White Paper, 2005). The article concludes with 2 preliminary recommendations for IRB reform.

Variation in Institutional Review Board Responses to a Standard, Observational, Pediatric Research Protocol

Multicenter studies are becoming more common, and variability in local institutional review board (IRB) assessments can be problematic. To investigate the variability of IRB responses to a multicenter observational study of children presenting to emergency departments. The authors collected the original IRB applications, subsequent correspondence, and a survey assessing submission timing and response and the nature of IRB queries. The study was conducted as part of the Emergency Medicine Network (http://www.emnet-usa.org). Of 37 sites initiating the IRB process, 34 (92%) participated in this IRB-approved study. Institutional review boards returned initial applications in a median of 19 days (IQR, 11-34 d), and 91% considered the protocol to be minimal risk. Of 34 submissions, 13 required no changes, 18 received conditional approvals, and 3 were deferred. The median time from initial submission to final approval was 42 days (IQR, 27-61 d). Seven sites did not participate in patient recruitment: two had institutional issues, one obtained IRB approval too late for participation, and four sites (12%) reported that IRB hurdles contributed to their lack of participation. Nonetheless, 68% of sites that recruited patients reported that the overall experience made them more likely to participate in future multicenter research. There was substantial variation in IRB assessment of a standard protocol in this study. The burden of the application process contributed to some investigators not participating, but the majority of investigators remain enthusiastic about multicenter research. A national IRB may streamline the review process and facilitate multicenter clinical research.