Additional Safety Information Research Articles

Filgotinib in Active Noninfectious Uveitis

Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. ClinicalTrials.gov Identifier: NCT03207815.

CAR T-cell therapies: Measuring the growing need for increasing long-term safety protocols.

e23047 Background: The CAR T-Cell market has grown significantly over the last five years with six products in the U.S. market covering a range of cancer types (DLBCL, FL, MCL, MM, ALL). The number of transplant centers certified for CAR T-Cell administration has also grown from 142 centers in Q4 2020 to 200 in Q4 2023. The FDA is currently investigating the safety of CAR T-Cell therapies due to the threat of secondary malignancies. CAR T-Cell patients are treated at advanced treatment centers but after they have completed therapy, they are often referred back to their original specialist for long-term monitoring. The purpose of this research is to measure if referring Oncologists have the information required to safely manage CAR T-Cell patients. Methods: This study followed market research best practices. The study was based on a survey of the BrandImpact panel of Oncologists who refer patients and a CAR T-Cell Panel of Oncologists who administer CAR T-Cell therapies. Results: The majority of referring Oncologists (61%) report they could use more information about CAR T-Cell therapies. When asked on an unaided basis what type of information they require, the most common request was for additional safety information (57%). At the same time, one-third of Oncologists treating CAR T-Cell patients at the advanced centers feel that there needs to be improved knowledge of the long-term safety aspects of CAR T-Cell therapies. When they resume monitoring CAR T-Cell patients, they would like to better understand the relevant long-term side effects and how they differ from the short-term side effects. Conclusions: Oncologists who refer CAR T-Cell patients report that they need more information; mainly around safety/side-effects. Of the Oncologists administering CAR T-Cell therapies, one-third feel there needs to be improved knowledge of the long-term safety issues. Consideration should be given to improving the level of educational information provided on this topic to improve CAR T-Cell patient outcomes. [Table: see text]

Abstract PS14-08: Safety evaluation from the KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract Background: In KEYNOTE-355 (NCT02819518), pembrolizumab (pembro) + chemotherapy (chemo) led to statistically significant and clinically meaningful improvements in PFS and OS (primary endpoints) vs placebo (pbo) + chemo in patients (pts) with previously untreated PD-L1 positive advanced TNBC (combined positive score ≥10). In the overall safety population at final analysis, treatment-related AEs occurred in 96.3% of pts in the pembro + chemo arm and 95.0% of pts in the pbo + chemo arm; immune-mediated AEs occurred in 26.5% and 6.4% of pts, respectively. We report additional safety information, beyond the already reported safety results, on immune-mediated AEs and management from the final analysis of KEYNOTE-355. Methods: Eligible pts were randomized 2:1 to receive pembro 200 mg or pbo Q3W for up to 35 cycles + investigator’s choice of nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin. Safety was assessed in all randomized pts who received ≥1 dose of study treatment. AEs were monitored throughout the study and for 30 d post-treatment (90 d for serious AEs). Results: At final analysis (data cut-off: June 15, 2021), median treatment duration was 6.1 (range, 0.0–48.8) mo in the pembro + chemo arm (n = 562) and 5.3 (range, 0.0–51.5) mo in the pbo + chemo arm (n = 281). Of 157 pts with immune-mediated AEs and infusion reactions in the pembro + chemo arm, 125 had grade 1-2 events and 32 had grade 3-4 events; none were grade 5. The most common immune-mediated AEs with pembro + chemo were hypothyroidism (15.8%) and hyperthyroidism (4.3%); infusion reactions occurred in 3.7% of pts (table). Of 89 pts with hypothyroidism, median time to onset was 105 d (range, 19–707 d) and 70 were treated with thyroid replacement, suggesting an endocrine abnormality and need for continued thyroid replacement. Of 24 pts with hyperthyroidism, median time to onset was 53.5 d (range, 20–209 d) and 2 were treated with corticosteroids. Of 21 pts with infusion reactions, median time to onset was 147 d (range, 1–729 d) and 10 were treated with corticosteroids. Other immune-mediated AEs of interest in the pembro + chemo arm were pneumonitis (2.5%) and adrenal insufficiency (1.4%); most of these events were grade 2–3. Of 14 pts with pneumonitis, median time to onset was 99.5 d (range, 29–288 d) and 11 were treated with corticosteroids; median episode duration was 56 d. All 8 pts with adrenal insufficiency were treated with hormone replacement. There were no reports of hypophysitis. Conclusion: In pts with previously untreated advanced TNBC, pembro + chemo had a manageable safety profile that was generally consistent with the known safety profiles of pembro and the chemo regimens. Most immune-mediated AEs and infusion reactions were grade 1-2, manageable with treatment interruption, corticosteroids, and/or hormone replacement therapy, and did not result in discontinuation of study treatment. Together with the efficacy findings, our results support pembro + chemo as a standard of care regimen for these pts. Table. Citation Format: Hope Rugo, Peter Schmid, Zbigniew Nowecki, David Cescon, Seock-Ah Im, Mastura Yusof, Carlos Gallardo, Hiroji Iwata, Carlos Barrios, Sherene Loi, Xuan Zhou, Xiaoli Zhang, Wilbur Pan, Vassiliki Karantza, Javier Cortés. Safety evaluation from the KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-08.

Effectiveness and safety of edaravone dexborneol in acute ischemic stroke (EXPAND): Study protocol for a prospective, multicenter, real-world cohort study

Background: Edaravone dexborneol has been confirmed as a novel neuroprotective agent by acting on multiple active targets of antioxidation and anti-inflammation. Objectives: This study aims to evaluate the effectiveness and safety of edaravone dexborneol in patients with acute ischemic stroke (AIS) within 14 days of symptom onset in real-world clinical practice. Methods: This prospective, multicenter, 2-arm, parallel, real-world cohort study will involve 72 stroke centers in China and plans to recruit 4750 exposed/unexposed patients with a 2:1 ratio to gather additional safety information on edaravone dexborneol. Patients eligible of the Effectiveness and Safety of Edaravone Dexborneol in Acute Ischemic Stroke (EXPAND) are diagnosed with AIS within 14 days of symptom onset. The eligible patients who receive edaravone dexborneol will be assigned to the exposed group, while those without using edaravone dexborneol will be assigned to the unexposed group. All participants will be followed up for 90 days. The primary outcome is a favorable functional outcome as defined by a modified Rankin Scale (mRS) score 0–1 at 90 days. Primary efficacy in the 2 groups will be compared using multivariable logistic regression. Results: EXPAND is the first real-world study to elucidate the efficacy and safety of edaravone dexbornel in AIS, which has the potential to extend the therapeutic time window of neuroprotective treatment and propose a multiple-target approach for AIS. Conclusions: The protocol was approved by the Ethics Committee at all participating sites [the reference number of central ethic committee: (2022)090] and by the local Institutional Review Board of each participating center. The findings of the study will be published in peer-reviewed scientific journals and presented at national and international conferences. This cohort study only collects real-world patient data during the diagnosis and treatment process. The refusal of a patient to participate or the decision to withdraw from the study will not interfere with the clinical decision-making. Thus, no additional risk will be imposed. Trial registration number: NCT05644223.

Ninety-day repeated dose toxicity of Ashwagandha (Withania somnifera) root extract in Wistar rats

Many pharmacological studies have been carried out to describe multiple biological properties of Ashwagandha (Withania somnifera) and the additional safety information on repeated dose toxicity is limited. Therefore, the aim of this study was to obtain safety data for KSM-66 Ashwagandha Root Extract (ARE) through repeated-dose toxicity in Wistar rats according to the Organisation for Economic Co-operation and Development (OECD) test guideline (TG 408). ARE was orally administered to rats at doses of 0, 500, 1000, and 2000 mg/kg body weight/day for 90-day and reversibility of effects of 0 and 2000 mg/kg body weight/day was assessed for 14 days. All the animals from treated, control, recovery control and recovery groups were observed for clinical signs of toxicity once daily, detailed clinical examination every week after dosing and before necropsy day. Mortality/Morbidity was observed twice daily. In addition, observations were noted in the detailed sensory reactivity, functional assessments, body weight, food consumption, ophthalmological examination, hematological parameters, biochemical parameters, organ weights, histopathological findings. The present results show that the no observed adverse effect level (NOAEL) of KSM-66 Ashwagandha Root Extract was considered to be 2000 mg/kg body weight/day in rats after repeated oral administration for 90-day under the present study conditions.

Automatic Extraction of Comprehensive Drug Safety Information from Adverse Drug Event Narratives in the Korea Adverse Event Reporting System Using Natural Language Processing Techniques.

Concerns have been raised over the quality of drug safety information, particularly data completeness, collected through spontaneous reporting systems (SRS), although regulatory agencies routinely use SRS data to guide their pharmacovigilance programs. We expected that collecting additional drug safety information from adverse event (ADE) narratives and incorporating it into the SRS database would improve data completeness. The aims of this study were to define the extraction of comprehensive drug safety information from ADE narratives reported through the Korea Adverse Event Reporting System (KAERS) as natural language processing (NLP) tasks and to provide baseline models for the defined tasks. This study used ADE narratives and structured drug safety information from individual case safety reports (ICSRs) reported through KAERS between 1 January 2015 and 31 December 2019. We developed the annotation guideline for the extraction of comprehensive drug safety information from ADE narratives based on the International Conference on Harmonisation (ICH) E2B(R3) guideline and manually annotated 3723 ADE narratives. Then, we developed a domain-specific Korean Bidirectional Encoder Representations from Transformers (KAERS-BERT) model using 1.2 million ADE narratives in KAERS and provided baseline models for the task we defined. In addition, we performed an ablation experiment to investigate whether named entity recognition (NER) models were improved when a training dataset contained more diverse ADE narratives. We defined 21 types of word entities, six types of entity labels, and 49 types of relations to formulate the extraction of comprehensive drug safety information as NLP tasks. We obtained a total of 86,750 entities, 81,828 entity labels, and 45,107 relations from manually annotated ADE narratives. The KAERS-BERT model achieved F1-scores of 83.81 and 76.62% on the NER and sentence extraction tasks, respectively, while outperforming other baseline models on all the NLP tasks we definedexcept the sentence extraction task. Finally, utilizing the NER model for extracting drug safety information from ADE narratives resulted in an average increase of 3.24% in data completeness for KAERS structured data fields. We formulated the extraction of comprehensive drug safety information from ADE narratives as NLP tasks and developed the annotated corpus and strong baseline models for the tasks. The annotated corpus and models for extracting comprehensive drug safety information can improve the data quality of an SRS database.

Effect of Prophylactic Fibrinogen Concentrate In Scoliosis Surgery (EFISS): a study protocol of two-arm, randomised trial

IntroductionFibrinogen is one of the essential coagulation factors. Preoperative lower plasma fibrinogen level has been associated with higher blood loss. Scoliosis surgery presents a challenge for the anaesthetic team, one...

Durable Responses from Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study

Introduction: R-CHOP remains the standard of care for DLBCL but fails in a proportion of patients (pts.) either through refractory lymphoma or relapse after achieving an initial remission. In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve the outcome for non-germinal centre like DLBCL. However, R-CHOP-I treated pts. who were aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R-CHOP alone. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R-CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. Therefore, we combined A with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy. Methods: Eligible pts. were treatment naive with histologically confirmed DLBCL. All received 6 cycles of R-CHOP on a standard 21-day schedule, with the addition of A in cycles 2-6. A continuation phase of A only, for 2 cycles of 28 days was administered after R-CHOP-A. The primary objective of the phase Ib was to establish a recommended phase II dose (RP2D) of A in combination with R-CHOP (modified 6+6 design) with 24 months follow-up. Phase II assessed the overall response rate (ORR) of the combination and ascertained additional safety information. Secondary endpoints included metabolic complete response rates (mCR), PFS and OS and their relation to the cell of origin (COO), pharmacokinetics and pharmacodynamics. COO was determined by HTG EdgeSeq transcriptome analysis. Recruitment of pts. over the age of 65 was suspended as an urgent safety measure (USM) following the abstract release of data from PHOENIX (Nov 2018). ACCEPT reopened to all ages after a comprehensive safety review by the Independent Data Monitoring Committee (Sep 2019). The trial was endorsed by CRUK (CRUKDE/16/006) and coordinated by Southampton Clinical Trials Unit. Results: From May 2017 to Jan 2020, 38 pts. were enrolled (safety population: pts. in receipt of any component of therapy). The median age was 64 years (range 24-80, 39% >65 years old); 76% stage III/IV; 71% abnormal LDH; 29% B symptoms; 34% bulk; 24% high IPI; 32% high-intermediate IPI. Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age >65 at time of USM, 1 pt). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The RP2D was chosen as 100mg bd acalabrutinib. The most common ≥grade3 adverse events were neutropenia (34% of pts.), febrile neutropenia (16%) and diarrhoea (11%). The most frequently reported serious adverse event was febrile neutropenia (13% of pts.). Age did not compromise the delivery of full dose R-CHOP in combination with A. One of 7 eligible pts. in the first cohort (A 100mg od) progressed on therapy and subsequently died, 1 pt. not achieving mCR received additional radiotherapy. Twenty-four eligible patients received the RP2D in either dose escalation or expansion. Four pts. withdrew early from treatment (1 pt subject withdrawal, 2 pts. investigator withdrawal and 1pt. due to toxicity) and are included in the efficacy analysis. The RP2D ORR was 96% (95% CI 79-100) with 79% (95% CI 58-93) of pts. achieving a mCR (4 pts. partial response (PR), 1pts. stable disease (SD)). One pt. with MYC/BCL2/BCL6 rearrangements and 1 pt. with MYC/BCL6 rearrangement achieved a mCR; neither have progressed. mCR was achieved in 9 of 12 ABC pts. (83%), 9/9 GCB pts and 1/2 unclassified pts. (PR 2, 0, 1 pts. respectively, 1/1 fail). At the RP2D with a median follow-up of 30 months, the 24 months EFS was 90% (95% CI 66-97), PFS was 95% (95% CI 68-99) and OS was 96% (95% CI 73-99) - 1 pt. progressed at 11 months and 1 double expressor patient with SD received subsequent chemotherapy prior to progression then died of PD. R-CHOP did not affect the pharmacokinetics of A. Additional translational data will be presented. Conclusions: Acalabrutinib is well tolerated in combination with R-CHOP chemotherapy and may be associated with improved efficacy. This is being explored in the randomised REMoDL-A (NCT04546620) and ESCALADE (NCT04529772) trials.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Repeated-dose 90-day oral toxicity study of GST in Sprague-Dawley rats.

TiO2 have been studied on inhalation and skin exposure due to the properties of the materials’ use (cosmetics, paints and other products) and the additional safety information on other intake routes for the potential risk assessment is limited. Therefore, the aim of this study was to obtain safety data for new TiO2 powder, GST produced through sludge recycling of the sewage treatment plant through repeated-dose toxicity in Sprague-Dawley (SD) rats in according to the OECD test guideline (TG 408). Based on the results of the dose-range finding study (28-day repeated toxicity), GST was orally administered to rats at doses of 0, 500, 1000, and 2000 mg/kg B.W/day for 90-day and reversibility of effects of 2000 mg/kg bw/day was assessed after 4 weeks. In clinical signs, compound-colored stool was observed in all animals of treatment group (low: day 14 or 15, middle: day 8, high: day 8) and continuously observed up to the end of administration or day 1 of recovery period (high dose group). Also, the test substance retention in gastro-intestinal tract was observed in all animals of treatment group in gross finding at necropsy and foreign materials in lumen of these organs (stomach, duodenum, ileum, cecum, colon, rectum) likely indicative for the presence of test material in histopathological examination. In addition, no test substance-related adverse effects were noted in the detailed clinical observations, sensory reactivity/functional assessments, body weight, food consumption, urinary analysis, ophthalmological examination, hematological/biochemical parameters, organ weights, histopathological findings. Therefore, the present results show that the NOAEL (no observed adverse effect level) of new TiO2 powder, GST was considered to be 2000 mg/kg B.W/day in rats after repeated oral administration for 90-day under the present study conditions and no target organs were identified.

Repeated-dose 28-day dermal toxicity study of TiO2 catalyst (GST) in Sprague-Dawley rats.

TiO2 have been studied on inhalation and skin exposure due to the properties of the materials’ use (cosmetics, paints and other products) and the additional safety information on other intake routes for the potential risk assessment is limited. The aim of this study was to obtain dose-range for subchronic study (repeated 90-day dermal toxicity) new TiO2 powder, GST produced through sludge recycling of the sewage treatment plant through repeated-dose toxicity in Sprague-Dawley (SD) rats. Three test groups for the GST were administered at 500, 1000, 2000 mg/kg B.W/day in addition to a control group (distilled water for injection). 5 male and 5 female rats were included in each group, and we examined the clinical signs, body weights, food consumption, necropsy (organ weights, macroscopic findings), hematological/biochemical parameters and histopathological findings (eye, skin). As a result of observations, there were no treatment-related effects including clinical signs, mortality, necropsy findings etc. Therefore, the present results suggest that the TiO2-related effects were not observed for dermal during 28-day and dose selection for repeated 90-day study was considered to be 500, 1000 and 2000 mg/kg B.W/day under the present study conditions.

Injuries and illnesses to children in commercial fishing in Alaska: A brief report.

Commercial fishing is the most hazardous occupation in the United States. While the epidemiology of adult injuries and fatalities are well documented, injuries to children (<18 years old) are not described. The purpose of this report was to describe the characteristics of nonfatal injuries to children involved in commercial fishing. Nonfatal commercial fishing injuries to children were identified in the Alaska Fishermen's Fund. The Alaska Fishermen's Fund is an emergency fund payor of last resort. Data on nonfatal injuries to victims aged 17 or younger were analyzed. Descriptive statistics were used to characterize demographics and injury characteristics. Forty-four nonfatal child injury claims were made between 2012 and 2016. The mean age at the time of claim was 15.6 years (SD = 1.8) and 84% were male. The most common types of injuries among children were sprains and strains and the most commonly injured body parts were upper extremities and the trunk. Most injuries occurred in salmon fisheries. Children are participating in commercial fishing. Based on the results of this analysis, children are also experiencing occupational injuries. The results of this analysis underscore the need for additional safety and health information, guidance for supervisors, and intervention to prevent injuries to children participating in commercial fishing.

Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study

Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study

Changes in processing and labelling of frozen chicken products available to consumers in Vancouver

Background: Between May 2017 and May 2019, 18 Salmonella outbreaks in Canada were linked to raw chicken, resulting in the recall of 13 chicken products. Most of these products contained frozen raw breaded chicken, such as chicken nuggets, chicken fries, and breaded chicken burgers. (Public Health Agency of Canada, 2019) These products are especially risky for consumers because they may appear precooked, resulting in inadequate food safety measures being taken. (Catford, Ganz, &amp; Tamber, 2017). Due to this concern, as of April 1, 2019, all frozen raw breaded chicken product manufacturers are required to follow one of four Salmonella control measures set out by the Canadian Food Inspection Agency (CFIA). The simplest option for processors is to precook their products to destroy Salmonella bacteria and produce a ready-to-eat product. (Government of Canada, Canadian Food Inspection Agency, &amp; Food Safety and Consumer Protection Directorate, 2019a) Methods: Data was collected from all frozen chicken products available at 14 retail locations in Metro Vancouver that were randomly selected in previous studies carried out in 2018 and 2019 by the British Columbia Centre for Disease Control (BCCDC) and British Columbia Institute of Technology (BCIT) students. The processing status of the products surveyed in this study (n=466) was compared to those collected in the previous studies done in 2018 and 2019, respectively (n=383; n=415). Other information collected included whether product packaging contained statements of internal temperature, requirements for thermometer use, and additional food safety instructions. Data on these parameters collected in the current study (n=466) were compared to similar data collected in 2008 (n=24) and in 2018 (n=67). Photos were taken of all product labels and relevant data from the photos was compiled in Microsoft Excel. Statistical analyses were done using chi-square tests performed using NCSS 2019 software. Results: The proportion of surveyed frozen chicken products that were cooked as opposed to raw increased from 38% in 2018 to 41% in 2019 to 69% in 2020. The proportion of products containing statements regarding required internal temperatures increased from 58% in 2008 to 96% in 2018 and then decreased to 86% in 2020. 0%, 4.5%, and 1.7% of products surveyed in 2008, 2018, and 2020, respectively, included an indication to use a food thermometer. 79%, 57%, and 25% of products surveyed in the same years included additional food safety statements. Conclusions: This study showed that the ratio of cooked to uncooked frozen chicken products available to consumers in the Metro Vancouver area has increased since the CFIA’s Salmonella control measure requirements for frozen breaded chicken manufacturers were implemented in 2019. The 28% and 26% increase since 2018 and 2019, respectively, suggests that many frozen chicken product manufacturers are complying with the CFIA requirements by using a validated cook process to reduce Salmonella in their products. This study also showed that, since 2019, there has been a significant decline in the proportion of frozen chicken products that contain information about internal cooking temperatures and additional food safety information on their packaging.

Risk assessment of the antifungal and insecticidal peptide Jaburetox and its parental protein the Jack bean (Canavalia ensiformis) urease

Jaburetox (JBTX) is an insecticidal and antifungal peptide derived from jack bean (Canavalia ensiformis) urease that has been considered a candidate for developing genetically modified crops. This study aimed to perform the risk assessment of the peptide JBTX following the general recommendations of the two-tiered, weight-of-evidence approach proposed by International Life Sciences Institute. The urease of C. ensiformis (JBU) and its isoform JBURE IIb (the JBTX parental protein) were assessed. The history of safe use revealed no hazard reports for the studied proteins. The available information shows that JBTX possesses selective activity against insects and fungi. JBTX and JBU primary amino acids sequences showed no relevant similarity to toxic, antinutritional or allergenic proteins. Additionally, JBTX and JBU were susceptible to in vitro digestibility, and JBU was also susceptible to heat treatment. The results did not identify potential risks of adverse effects and reactions associated to JBTX. However, further allergen (e.g. serum IgE binding test) and toxicity (e.g. rodent toxicity tests) experimentation can be done to gather additional safety information on JBTX, and to meet regulatory inquiries for commercial approval of transgenic cultivars expressing this peptide.

Real-life safety of 5-grass pollen tablet in 5-to-9-year-old children with allergic rhinoconjunctivitis

BackgroundAlthough 5-grass pollen sublingual immunotherapy has a good safety profile in controlled clinical trials, additional safety information among pediatric patients in a real-world setting would be useful. ObjectiveTo further document the safety of 5-grass tablet among children aged 5 to 9 years with allergic rhinoconjunctivitis (ARC). MethodsThis multicenter, observational study included allergy immunotherapy-naïve 5- to 9-year-old children with grass pollen–induced ARC prescribed with 5-grass tablet daily (3-day dose escalation to 300 index of reactivity [IR]). Patients were followed up daily for safety and tolerability over the first 30 treatment days. Adverse events (AEs) and adverse drug reactions (ADRs) were analyzed descriptively. ResultsThree hundred seven children (mean age, 7.1 years) were enrolled. Fifty-eight percent were confirmed as polysensitized, and 36% had mild-to-moderate asthma. Of 307 patients, 233 (76%) reported AEs, and 173/307 (56%) reported ADRs, most frequently mild application-site reactions (throat irritation, oral pruritus, oral paresthesia). Sixteen of 307 (5.2%) patients withdrew because of ADRs. In 143 of 173 (83%) patients, ADRs first occurred within 1 week of starting treatment. More than half of the ADRs lasted less than 2 days, and ADRs resolved spontaneously in 161 of 173 (93%) patients. Recurrences of ADRs were reported in 45 of 173 (26%) patients and were also mainly application-site reactions. No notable differences were found in ADRs related to whether patients had asthma at inclusion. Neither epinephrine use nor admission to intensive care unit was reported. ConclusionThe safety profile of 5-grass tablet in pediatric ARC patients aged 5 to 9 years was consistent with safety findings in older patients, most ADRs being at the application site and mild to moderate. ClinicalTrials.gov identifier: NCT02295969; EUPAS registration number: 8104.

Psychiatric adverse events and effects on mood with prolonged-release naltrexone/bupropion combination therapy: a pooled analysis

Background/objectivesProlonged-release (PR) naltrexone 32 mg/bupropion 360 mg (NB) is approved for chronic weight management as an adjunct to reduced-calorie diet and increased physical activity. Central nervous system-active medications have the potential to affect mood; therefore, post hoc analysis of clinical trial data was conducted to evaluate psychiatric adverse events (PAEs) and effects on mood of NB therapy versus placebo.Subjects/methodsData were pooled from 5 prospective, double-blind, randomized, placebo-controlled clinical trials (duration range, 24–56 weeks) of NB in subjects with overweight or obesity. PAEs were collected via AE preferred terms, organized into major subtopics (e.g., anxiety, depression, sleep disorders), and divided into category terms (e.g., anxiety, potential anxiety symptoms). Additionally, the Inventory of Depressive Symptomatology Self Report (IDS-SR; score range 0–84) and the Columbia Classification Algorithm of Suicide Assessment (C-CASA) evaluated treatment-emergent depressive/anxiety symptoms and suicidal behavior/ideation, respectively.ResultsBaseline characteristics and comorbidities were comparable for placebo (n = 1515) and NB (n = 2545). Most common PAEs in the NB group (using category grouping; NB vs placebo) were sleep disorders (12.7 vs 7.9%, P < 0.001), anxiety (5.4 vs 3.3%, P = 0.029), and depression (1.8 vs 2.7%, P = 0.014); PAEs were more frequent during dose escalation and generally mild or moderate. Mean (SD) changes in IDS-SR total score from baseline to endpoint were small in both groups: 0.13 (5.83) for NB and −0.45 (5.65) for placebo. Retrospective AE categorization via C-CASA confirmed no completed suicides, suicide attempts, or preparatory acts toward imminent suicidal behavior.ConclusionsThis large pooled analysis of 5 clinical trials provides additional safety information about the NB PAE profile. Anxiety and sleep disorder-related PAEs were more frequent with NB versus placebo but were mostly mild to moderate and generally occurred early. Depression-related PAEs were less common with NB than placebo, and NB was not associated with suicidal ideation or behavior in this patient population.

Persistent Fracture Reduction with Abaloparatide-SC (TYMLOS™) Followed by 24 Months of Alendronate

Introduction In the ACTIVE phase III trial, 2463 postmenopausal women with osteoporosis were randomized 1:1:1 to abaloparatide (ABL; n=824), blinded placebo (PBO; n=821), or open-label teriparatide (n=818). During ACTIVE, ABL increased BMD and reduced vertebral, nonvertebral, clinical, and major osteoporotic fractures compared to PBO. Women who completed ABL or PBO treatment in ACTIVE were eligible to enroll in an extension study (ACTIVExtend) to receive up to 24 months of open-label alendronate (ALN). Objectives To provide additional safety information and to evaluate vertebral and nonvertebral fracture endpoints. Methods The ACTIVExtend study enrolled 558 women from the original ABL group and 581 from the PBO group of the ACTIVE study (92% of women who completed ABL or PBO treatment in ACTIVE). Pre-specified endpoints, including vertebral, nonvertebral, clinical, and major osteoporotic fractures, were assessed over the 43-month period from ACTIVE baseline to the end of ACTIVExtend (18 months of ABL or PBO treatment, 1 month for reconsent, and 24 months of ALN treatment). Nonvertebral fracture endpoints were assessed using the Kaplan-Meier (KM) method, proportional hazard model, and logrank test for patients enrolled in ACTIVExtend and for the full ITT population randomized to ABL or PBO treatment in ACTIVE. Results During the 43-month period, 5.6% (n=32) of evaluable women sustained a new morphometric vertebral fracture in the PBO followed by ALN (PBO/ALN) group compared to 0.9% (n=5) in the ABL/ALN group, an 84% relative risk reduction (p The Table shows the KM rates of nonvertebral fracture endpoints over 43 months from ACTIVE baseline through the end of ACTIVExtend for both the ACTIVExtend cohorts as well as the full ACTIVE ITT population. The incidence of adverse events (AEs) including severe and serious AEs during ALN treatment period was similar for both study groups. The most common AEs were arthralgia, URI, and back pain. No cases of atypical femoral fracture or osteonecrosis of the jaw were reported. Conclusions In the ACTIVExtend study, administration of ABL for 18 months followed by ALN for 24 months resulted in sustained vertebral and nonvertebral fracture reduction compared to PBO followed by ALN. In the full randomized ACTIVE ITT population, over 43 months, in the ABL + ABL/ALN groups, there was a significant reduction in the incidence of vertebral and nonvertebral fractures as well as hip fractures compared to the PBO + PBO/ALN groups.

Abstract CT162: ACCEPT: A phase Ib/II combination of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL)

Abstract Background DLBCL is the most common non-Hodgkin lymphoma (NHL) comprising one third of all adult NHL cases, accounting for an annual incidence in the UK of approximately 5,000 patients. R-CHOP has been accepted as the international standard first-line regimen, with cure rates of around 60-70%. There is a need to further improve efficacy of first line treatment. Chronic and tonic B-cell receptor (BCR) signaling has been identified as a feature of DLBCL. Preclinical models of this lymphoma have demonstrated cytotoxicity through interruption of BCR-signaling. Inhibition of Bruton's tyrosine kinase (BTK), downstream of the BCR has proven active clinical trials in DLBCL, particularly in the activated B-cell subtype. The second generation BTK inhibitor, acalabrutinib, has demonstrated improved target specificity and bioavailability, with potential for better efficacy and tolerability compared to earlier agents. It is appealing to combine this targeted agent with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy. Method Patients must be 16 years or older, treatment naive with histologically confirmed DLBCL. All will receive 6 cycles of R-CHOP chemotherapy on a standard 21-day schedule, with the addition of acalabrutinib in cycles 2-6, to allow determination of the subtype by whole transcriptome gene expression profiling during cycle 1. This will be followed by a continuation phase of acalabrutinib only, for 2 cycles of 28 days. The primary objective of the phase I is to establish a recommended phase II dose of acalabrutinib in combination with R-CHOP. The primary objective of the phase II is to assess activity of the combination (by overall response rate) and determine additional safety information. Secondary endpoints include duration of response, PFS and OS and their relation to the cell of origin subtype, and BTK receptor occupancy in peripheral blood mononuclear cells and tumor measured by a drug analogue enzyme-linked immunosorbent assay. The effect of acalabrutinib on antibody-directed cellular cytotoxicity mediated by rituximab will be measured in vitro during treatment. The trial is coordinated by the Cancer Research UK Southampton Clinical Trials Unit. It will recruit up to 24 patients during phase I in a modified classical 6+6 design, and 15 patients during phase II. This is an investigator initiated study that has been granted free access to investigational medicinal product, trial Management and translational study support through a grant from Acerta Pharma B.V. (IST-LY-801) and has endorsement from Cancer Research UK (CRUKDE/16/006). Trial registration: ISRCTN11965217 Progress Phase I of the study opened in April 2017 and has recruited 6 eligible patients to the first cohort at a dose of 100mg acalabrutinib once daily, with a further 4 patients recruited to the second cohort at a dose of 100mg twice daily. Citation Format: Peter W M Johnson, Joshua Caddy, Tom Cumin, Bridgen Merton, Tom Maishman, Angelic Galanopoulou, Gareth Griffiths, Andrew Davies. ACCEPT: A phase Ib/II combination of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT162.

Concerns for Bleeding in the Elderly with the Use of Direct Oral Anticoagulants.

Since Food and Drug Administration approval of dabigatran in 2010, direct oral anticoagulants (DOACs) have been alternatives to warfarin for patients who are at risk for cardioembolic complications of nonvalvular atrial fibrillation. Unfortunately, there are limited safety data available on the use of these newer agents in older adults, particularly risks of gastrointestinal, intracranial, and major bleeding (as defined by the International Society on Thrombosis and Haemostasis) in those 75 years of age and older. The purpose of this manuscript is to provide a review of available literature regarding the risk of bleeding in older adults for each DOAC based on available retrospective cohort, secondary, and subgroup analyses, and to highlight the need for additional safety information in this population.