Risk Of Serious Adverse Events Research Articles

Fecal Microbiota Transplant in Pediatric Solid Organ Transplant Recipients.

Fecal microbiota transplant (FMT) is an effective treatment for recurrent Clostridioides difficile infection (CDI). Safety concerns around FMT are increased in immunocompromised populations, such as solid organ transplant (SOT) recipients. Outcomes among adult SOT recipients suggest FMT is efficacious and safe; however, pediatric SOT data are lacking. We describe the efficacy and safety of FMT among pediatric SOT recipients in a single-center retrospective study from March 2016 to December 2019. Successful FMT was defined as no recurrence of CDI within 2 mo of FMT. We identified 6 SOT recipients ages 4-18 y who received FMT a median of 5.3 y post-SOT. Success after a single FMT was 83.3%. One liver recipient did not achieve cure after 3 FMTs and remains on low-dose vancomycin. One serious adverse event (SAE) occurred; cecal perforation and bacterial peritonitis occurred following colonoscopic FMT coordinated with intestinal biopsy in a kidney transplant recipient. He achieved full recovery and CDI cure. There were no other SAEs. There were no adverse events related to immunosuppression or transplantation status including: bacteremia, cytomegalovirus activation or reactivation, allograft rejection, or allograft loss. In this limited series, efficacy of FMT in pediatric SOT is comparable to efficacy in the general pediatric recurrent CDI population. There may be an increased risk of procedure-related SAE in SOT patients and larger cohort studies are needed.

The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

Abstract #1402502: Hypercalcemia of Malignancy in Pregnancy, a Management Dilemma

Hypercalcemia of Malignancy (HCM) is a complication that is typically managed with bisphosphonates (BP). However, BP are not studied in pregnant patients with HCM and avoided due to potential adverse outcomes on mother and fetus thus limiting available options to manage hypercalcemia in pregnancy. We describe a case of HCM in a pregnant patient managed with Zoledronic acid. 36-year-old female, 32 weeks pregnant diagnosed during pregnancy with stage IV Breast cancer with liver and bone metastases, was admitted with hypercalcemia with no previous history. She did not have renal stones, polyuria, constipation, bone pain, fractures or taking calcium supplements. Lab data showed high calcium 12.9mg/dl, low PTH 5pg/ml, 25-OH vitamin D 15.5ng/ml, 1,25 OH vitamin D 70.28pg/ml, high PTHrP 6.1pmol/L. She received IV fluids and calcitonin with minimal benefit. After weighing risks and benefit and discussion with other teams, she was given IV Zoledronic acid. With chemotherapy and hypercalcemia, she developed severe emesis and decreased oral intake resulting in dehydration, low magnesium and phosphorus. She developed arrhythmia, frequent uterine contractions and fetal tachycardia and was treated for preterm labor with steroids, penicillin prophylaxis, aggressive hydration, and electrolyte replacement. Preterm delivery was safely avoided. After 4 days of BP dose, calcium normalized to 8.2 mg/dL and she was stable to be discharged home. She later received second cycle of chemotherapy and had uncomplicated vaginal delivery at 38 weeks with no neonatal complications. There are few studies on use of BP in pregnancy showing no increased risk of serious adverse effects. A systematic review of 51 cases with exposure to BP before or during pregnancy did not result in skeletal abnormalities or congenital malformations in the infants. In another case control study of 36 women with BP exposure, no major teratogenic effects were found but rates of neonatal complications were increased in women with systemic diseases, as were spontaneous abortions for women with bone disease. One case of 24 weeks pregnant female with metastatic breast cancer, pamidronate improved HCM and uterine contractions with no adverse effects on neonate. In our patient, treating hypercalcemia was necessary to avoid severe complications. We treated her with zoledronic acid as it is more effective then pamidronate at normalizing calcium and has similar safety profile. We optimized hydration status and monitored electrolytes to mitigate risk of side effects expected from BP use with good maternal and fetal results. More studies are required to determine safe use of BP in pregnant patients to guide management and avoid complications of HCM in mother and fetus.

Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis.

Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. None.

195P Impact of an interactive eHealth system for patient reported outcomes on safety in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer treated by palbociclib and endocrine therapy

CDK 4/6 inhibitors play an important role in hormone receptor (HR)-positive, HER2-negative advanced and metastatic breast cancer. Oral medications such as palbociclib offer advantages but pose a challenge for therapy adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the quality of life (QoL) status of the patient continuously throughout the course of treatment and, ideally, providing a basis for intensified care when indicated. PreCyle (NCT03220178) is a multicenter, randomized phase IV Intergroup trial to evaluate the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with HR+ HER2-, locally advanced or metastatic breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1; stratified by line of treatment) to the active arm A (supported by CANKADO PRO-React) or the inform arm B (drug intake documentation only). This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account. The safety population comprised 318 patients in Arm A (23.3% SAEs) and 161 in arm B (31.1% SAEs). While distributions of adverse events (AEs) were similar by arm on the whole, patients in the CANKADO active arm had a favorable hazard ratio of 0.67 (95%-CI: 0.46-0.97; p=.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. Safety analysis of the PreCycle trial demonstrates for the first time in a randomized prospective trial that interactive eHealth-based support has a substantial favorable impact on the risk of SAEs for patients with advanced and metastatic HR+/HER2- breast cancer on oral tumor therapy. While eHealth-based support may not prevent adverse events, CANKADO PRO-React could mitigate their progression to a serious adverse event, thus resulting in a substantial QoL benefit for patients.

Abstract #1406144: Safety and Efficacy of SGLT2 Inhibitors Use in Patient with Diabetes After Renal Transplant

The sodium glucose cotransporter2 inhibitors (SGLT2i) are preferred anti-glycemic agents for patients with diabetes mellitus (DM) and chronic kidney disease (CKD). These agents have been shown to slow the progression of kidney disease. There is limited experience of SGLT2i in renal transplantation (RT). Concerns have been that the glycosuria induced osmotic diuresis might cause a decrease in renal perfusion and there might be a possible increased risk of urinary tract infections (UTI). We therefore performed a retrospective review of data of patients with DM and RT treated with SGLT2i compared to those without SGLT2i. The primary outcome was the change in eGFR or serum creatinine at 1-year. Secondary outcomes were documentations of serious adverse events (SAE). Data were retrieved from the electronic medical record of a Midwestern academic medical center using the program Epic and the sub-program Slicer/ Dicer. The search algorithm inclusion criteria were: “Diabetes Mellitus” “kidney transplant”, and “medicine: sodium glucose transport inhibitor”, which resulted in an inclusion of 44 patients in the “SGLT2i group”. A comparator group of patients with DM and RT who matched the above screening criteria (except for SGLT2i use), was then retrieved. We then devised a propensity score by performing a multivariate regression analysis with the covariates of age, type of transplant, duration of transplantation, and baseline eGFR. Data from 44 patients on SGLT2i were closely matched (by standardized effects size) for age, estimated GFR, duration and source of transplant with 70 control patients with DM and RT who were not on SGLT2i. Weight changed in SGLT2i group from baseline at 3, 6 and 12months (by -4.1 ± 3.3 kg, -5.1 ± 5.0 kg and -5.2 ± 6.5 kg) and did not change in controls (p [ANOVA, drug] = 0.009). There was no significant difference at 3, 6 or 12 months in changes in: A1c, systolic or diastolic blood pressure, hematocrit, hemoglobin, total cholesterol, LDL cholesterol, HDL cholesterol, or serum triglycerides. There were no documented significant increases in SAE in those on SGLT2i compared with controls in hospitalizations for acute kidney injury, episodes of acute transplant rejections, amputations, cellulitis, diabetic ketoacidosis, or outpatient treatment for urinary tract infections, or genital mycotic infections. Use of SGLT2i in patients with diabetes and renal transplant showed beneficial effect in reducing weight without a higher risk of SAE. Longer follow up may be necessary to define the impact on eGFR.

Fecal transplantation for treatment of inflammatory bowel disease.

Fecal transplantation for treatment of inflammatory bowel disease.

Efficacy, safety, and tolerability of antimicrobial agents for complicated intra-abdominal infection: a systematic review and network meta-analysis

BackgroundWhich antimicrobial agents provide the optimal efficacy, safety, and tolerability for the empirical treatment of complicated intra-abdominal infection (cIAI) remains unclear but is paramount in the context of evolving antimicrobial resistance. Therefore, updated meta-analyses on this issue are warranted.MethodsWe systematically searched four major electronic databases from their inception through October 2022. Randomized controlled trials examining antimicrobial agents for cIAI treatment were included. Two reviewers independently assessed the quality of included studies utilizing the Cochrane Collaboration’s risk of bias tool as described in the updated version 1 of the Cochrane Collaboration Handbook and extracted data from all manuscripts according to a predetermined list of topics. All meta-analyses were conducted using R software. The primary outcome was clinical success rate in patients with cIAIs.ResultsForty-five active-controlled trials with low to medium methodological quality and involving 14,267 adults with cIAIs were included in the network meta-analyses. The vast majority of patients with an acute physiology and chronic health evaluation II score < 10 had low risk of treatment failure or death. Twenty-one regimens were investigated. In the network meta-analyses, cefepime plus metronidazole was more effective than tigecycline and ceftolozane/tazobactam plus metronidazole (odds ratio [OR] = 1.96, 95% credibility interval [CrI] 1.05 ~ 3.79; OR = 3.09, 95% CrI 1.02 ~ 9.79, respectively). No statistically significant differences were found among antimicrobial agents regarding microbiological success rates. Cefepime plus metronidazole had lower risk of all-cause mortality than tigecycline (OR = 0.22, 95% CrI 0.05 ~ 0.85). Statistically significant trends were observed favoring cefotaxime plus metronidazole, which exhibited fewer discontinuations because of adverse events (AEs) when compared with eravacycline, meropenem and ceftolozane/tazobactam plus metronidazole (OR = 0.0, 95% CrI 0.0 ~ 0.8; OR = 0.0, 95% CrI 0.0 ~ 0.7; OR = 0.0, 95% CrI 0.0 ~ 0.64, respectively). Compared with tigecycline, eravacycline was associated with fewer discontinuations because of AEs (OR = 0.17, 95% CrI 0.03 ~ 0.81). Compared with meropenem, ceftazidime/avibactam plus metronidazole had a higher rate of discontinuation due to AEs (OR = 2.09, 95% CrI 1.0 ~ 4.41). In pairwise meta-analyses, compared with ceftriaxone plus metronidazole, ertapenem and moxifloxacin (one trial, OR = 1.93, 95% CI 1.06 ~ 3.50; one trial, OR = 4.24, 95% CI 1.18 ~ 15.28, respectively) were associated with significantly increased risks of serious AEs. Compared with imipenem/cilastatin, tigecycline (four trials, OR = 1.57, 95%CI 1.07 ~ 2.32) was associated with a significantly increased risk of serious AEs. According to the surface under the cumulative ranking curve, Cefepime plus metronidazole was more likely to be optimal among all treatments in terms of efficacy and safety, tigecycline was more likely to be worst regimen in terms of tolerability, and eravacycline was more likely to be best tolerated.ConclusionThis study suggests that cefepime plus metronidazole is optimal for empirical treatment of patients with cIAIs and that tigecycline should be prescribed cautiously considering the safety and tolerability concerns. However, it should be noted that data currently available on the effectiveness, safety, and tolerability of antimicrobial agents pertain mostly to lower-risk patients with cIAIs.

The association between antihypertensive treatment and serious adverse events by age and frailty: A cohort study.

Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with frailty. This study aimed to examine this association using nationally representative electronic health record data. This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out. Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.

Safety and effectiveness of vaccines against COVID-19 in children aged 5–11 years: a systematic review and meta-analysis

To date, more than 761 million confirmed SARS-CoV-2 infections have been recorded globally, and more than half of all children are estimated to be seropositive. Despite high SARS-CoV-2 infection incidences, the rate of severe COVID-19 in children is low. We aimed to assess the safety and efficacy or effectiveness of COVID-19 vaccines approved in the EU for children aged 5-11 years. In this systematic review and meta-analysis, we included studies of any design identified through searching the COVID-19 L·OVE (living overview of evidence) platform up to Jan 23, 2023. We included studies with participants aged 5-11 years, with any COVID-19 vaccine approved by the European Medicines Agency-ie, mRNA vaccines BNT162b2 (Pfizer-BioNTech), BNT162b2 Bivalent (against original strain and omicron [BA.4 or BA.5]), mRNA-1273 (Moderna), or mRNA-1273.214 (against original strain and omicron BA.1). Efficacy and effectiveness outcomes were SARS-CoV-2 infection (PCR-confirmed or antigen-test confirmed), symptomatic COVID-19, hospital admission due to COVID-19, COVID-19-related mortality, multisystem inflammatory syndrome in children (MIS-C), and long-term effects of COVID-19 (long COVID or post-COVID-19 condition as defined by study investigators or per WHO definition). Safety outcomes of interest were serious adverse events, adverse events of special interest (eg, myocarditis), solicited local and systemic events, and unsolicited adverse events. We assessed risk of bias and rated the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluation approach. This study was prospectively registered with PROSPERO, CRD42022306822. Of 5272 screened records, we included 51 (1·0%) studies (n=17 [33%] in quantitative synthesis). Vaccine effectiveness after two doses against omicron infections was 41·6% (95% CI 28·1-52·6; eight non-randomised studies of interventions [NRSIs]; CoE low), 36·2% (21·5-48·2; six NRSIs; CoE low) against symptomatic COVID-19, 75·3% (68·0-81·0; six NRSIs; CoE moderate) against COVID-19-related hospitalisations, and 78% (48-90, one NRSI; CoE very low) against MIS-C. Vaccine effectiveness against COVID-19-related mortality was not estimable. Crude event rates for deaths in unvaccinated children were less than one case per 100 000 children, and no events were reported for vaccinated children (four NRSIs; CoE low). No study on vaccine effectiveness against long-term effects was identified. Vaccine effectiveness after three doses was 55% (50-60; one NRSI; CoE moderate) against omicron infections, and 61% (55-67; one NRSI; CoE moderate) against symptomatic COVID-19. No study reported vaccine efficacy or effectiveness against hospitalisation following a third dose. Safety data suggested no increased risk of serious adverse events (risk ratio [RR] 0·83 [95% CI 0·21-3·33]; two randomised controlled trials; CoE low), with approximately 0·23-1·2 events per 100 000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4·6 [0·1-156·1]; one NRSI; CoE low), with 0·13-1·04 observed events per 100 000 administered vaccines. The risk of solicited local reactions was 2·07 (1·80-2·39; two RCTs; CoE moderate) after one dose and 2·06 (1·70-2·49; two RCTs; CoE moderate) after two doses. The risk of solicited systemic reactions was 1·09 (1·04-1·16; two RCTs; CoE moderate) after one dose and 1·49 (1·34-1·65; two RCTs; CoE moderate) after two doses. The risk of unsolicited adverse events after two doses (RR 1·21 [1·07-1·38]; CoE moderate) was higher among mRNA-vaccinated compared with unvaccinated children. In children aged 5-11 years, mRNA vaccines are moderately effective against infections with the omicron variant, but probably protect well against COVID-19 hospitalisations. Vaccines were reactogenic but probably safe. Findings of this systematic review can serve as a basis for public health policy and individual decision making on COVID-19 vaccination in children aged 5-11 years. German Federal Joint Committee.

Abstract 3212: OQL06x, a gut-restricted janus kinase inhibitor to control epidermal growth factor receptor inhibitor-induced diarrhea

Abstract Background: Epidermal growth factor receptor inhibitors (EGFRIs) are widely used; however, therapy-related adverse effects (AEs) are common with diarrhea being the most frequent (e.g., afatinib up to 90% for all grades). Currently, there is no effective treatment or prevention, and severe diarrhea (~30%) results in EGFRi dose reduction or discontinuation. EGFRIs disrupt the gut epithelium and induce an inflammatory response characterized by cytokine release and neutrophil and T-cell infiltration. Janus kinase inhibitors (JAKIs) are immunosuppressive drugs and a candidate treatment for EGFRi-associated inflammation/diarrhea. However, oral JAKIs are associated with serious AEs (e.g., CV events, VTE, cancer, infections) and may lead to EGFR inhibitor resistance. We developed a gut-restricted JAKI with minimal systemic exposure that may reduce AEs and decrease the incidence of EGFRi-induced diarrhea. Methods: Multiple compounds were tested in vitro for their physiochemical properties (e.g., solubility, stability, and enzyme activity) and potential for inhibiting the activation of the JAK pathway and subsequent signal transducers transcription 3 (STAT3) after cytokine IL-6 activation in human peripheral blood mononuclear cells (hPBMC). Selected compounds were tested in vivo with afatinib (40mg/kg) plus OQL06x, tofacitinib, or placebo started on Day 1 and continued for 10 days in a rat EGFRi-induced diarrhea model. Orally administered OQL06x pharmacokinetics (PK) were tested in mice (5-25 mg/kg) and rats (2-5 mg/kg). Oral tofacitinib was used as a control. Results: OQL06x demonstrated favorable pharmaceutical properties and superior JAK enzyme inhibition (e.g., IC50: JAK1: OQL06x 0.06nM vs. tofacitinib 1.4nM). In vitro, hPBMC treated with OQL06x vs. tofacitinib showed greater inhibition of the IL-6, JAK-induced STAT3 activation (IC50: OQL06x 30nM vs. tofacitinib 222nM). OQL06x and tofacitinib showed a significant decrease in diarrhea compared with placebo control (both reduced diarrhea grade by 1.4 units vs. control, p &amp;lt; 0.01, two-way ANOVA). OQL06x was gut-specific vs. tofacitinib, with a significantly higher gut:blood ratio of up to 2000:1 vs. tofacitinib up to 20:1, p &amp;lt; 0.001, two-way ANOVA). Importantly, low bioavailability of OQL06x was found in both mouse (1.50%) and rat (0.23%) models demonstrating OQL06x’s limited systemic exposure. Moreover, no CYP inhibition was found (IC50 &amp;gt; 50µM), which favors a low drug-drug interaction potential. Conclusion: Our research demonstrated that an orally administered, gut-restricted JAK inhibitor, OQL06x, can reduce EGFR inhibitor-induced diarrhea severity. Additionally, OQL06x’s gut restriction and low systemic exposure may reduce the risk of serious AEs observed with other oral JAK inhibitors and limit the potential for interference with EGFR inhibition anti-cancer efficacy. Citation Format: Chengguang Wu, Kun Fang, Wenqin Zeng, Wenxi Li, Shilan Liu, Qing You, Robert Claude Tyler, Jie Luo, Shiyi Zhang, Hong Tang. OQL06x, a gut-restricted janus kinase inhibitor to control epidermal growth factor receptor inhibitor-induced diarrhea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3212.

Pharmacological Strategies for Bipolar Disorders in Acute Phases and Chronic Management with a Special Focus on Lithium, Valproic Acid, and Atypical Antipsychotics.

Bipolar disorders (BDs) are a heterogeneous group of severe affective disorders generally described by the alternation of (hypo)manic, depressive, and mixed phases, with euthymic intervals of variable duration. BDs are burdened with high psychiatric and physical comorbidity, increased suicide risk and reduced life expectancy. In addition, BDs can progress into complicated forms (e.g., mixed states, rapid/irregular cycling), which are more difficult to treat and often require personalized pharmacological combinations. Mood stabilizers, particularly Lithium and Valproic acid (VPA), still represent the cornerstones of both acute and chronic pharmacotherapies of BDs. Lithium is the gold standard in BD-I and BDII with typical features, while VPA seems more effective for atypical forms (e.g., mixed-prevalence and rapid-cycling). However, despite appropriate mood stabilization, many patients show residual symptoms, and more than a half recur within 1-2 years, highlighting the need of additional strategies. Among these, the association of atypical antipsychotics (AAPs) with mood stabilizers is recurrent in the treatment of acute phases, but it is also being growingly explored in the maintenance pharmacotherapy. These combinations are clinically more aggressive and often needed in the acute phases, whereas simplifying pharmacotherapies to mood stabilizers only is preferable in the long-term, whenever possible. When mood stabilizers are not enough for maintenance treatment, Quetiapine and, less consistently, Aripiprazole have been proposed as the most advisable adjunctive strategies, for their safety and tolerability profiles. However, in view of the increased risk of serious adverse effects, a careful patient-centered balance between costs and benefits is mandatory.

Successful re-intervention using endoscopic ultrasound-guided drainage via an endoscopic tapered sheath for recurrent walled-off necrosis with fibrosis.

Patients with disconnected pancreatic duct syndrome recur with pancreatic fluid collection in 17–38 % of cases after transmural stent removal [1] [2]. Symptomatic patients require endoscopic re-intervention; however, an approach via the same puncture route is often complicated by fibrosis caused by previous treatment. Long-term placement of a plastic stent is recommended for endoscopic ultrasound-guided drainage of a recurrent walled-off necrosis (WON). However, commonly used pigtail stents are difficult to pass through a fistula even post-dilation, especially in fibrotic cases. Lumen-apposing metal stents can be easily employed in such cases, albeit with an increased risk of serious adverse events in long-term placements [3] [4]. We report a successful re-intervention using endoscopic ultrasound-guided drainage via an endoscopic tapered sheath (EndoSheather; Piolax, Inc., Kanagawa, Japan) ([Fig. 1]) for a recurrent WON with fibrosis.

Matching-Adjusted Indirect Comparisons of Filgotinib vs Vedolizumab, Tofacitinib, and Ustekinumab for Moderately to Severely Active Ulcerative Colitis.

Where head-to-head trials are lacking, indirect comparative effectiveness can aid treatment decisions. We conducted matching-adjusted indirect comparisons of clinical outcomes with filgotinib vs recently approved comparators (vedolizumab, tofacitinib, ustekinumab) in patients with moderately to severely active ulcerative colitis (UC). Individual patient data from the SELECTION trial (NCT02914522) for filgotinib 200 mg were weighted to match average baseline characteristics of active treatment and placebo arms in comparator trials. Efficacy outcomes were compared for biologic-naive and biologic-experienced subgroups in induction and maintenance populations, if data were available. Safety and health-related quality of life outcomes were compared in the overall maintenance population. Filgotinib had a similar effect on efficacy outcomes compared with tofacitinib, ustekinumab, and subcutaneous vedolizumab in both the induction and maintenance populations. Filgotinib showed improved clinical response vs intravenous (IV) vedolizumab (odds ratio, 2.4; 95% confidence interval [CI], 1.0 to 5.5; P < .05) among the biologic-experienced induction population, and improved corticosteroid-free clinical remission (odds ratio, 15.2; 95% CI, 1.6 to 139.9; P < .05) among the biologic-naive maintenance population. Improved efficacy outcomes were reported with filgotinib compared with ustekinumab among the maintenance population. Higher estimates of serious adverse events were reported for filgotinib compared with vedolizumab IV 300 mg and tofacitinib 5 mg; however, imbalances were noted in their placebo groups. Health-related quality of life outcomes were similar between filgotinib and comparators. Matching-adjusted indirect comparison results suggest superiority of filgotinib 200 mg over vedolizumab IV in terms of clinical response and corticosteroid-free clinical remission in certain patient populations, noting small sample sizes and wide CIs, which may aid the selection of advanced therapies for moderately to severely active UC. A potential increased risk of serious adverse events was reported for filgotinib 200 mg vs vedolizumab IV and tofacitinib 5 mg, but findings should be interpreted with caution owing to underlying imbalances observed between the placebo groups of SELECTION and comparator trials.

Clinical Trials Portfolio and Regulatory History of Idelalisib in Indolent Non-Hodgkin Lymphoma

Idelalisib is a first-in-class phosphatidylinositol 3-kinase inhibitor that received US Food and Drug Administration accelerated approval in July 2014 as a single-agent treatment for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Serious adverse effects were reported in 2016 leading to termination of postmarketing registry trials. However, idelalisib remained on the market until 2022 when Gilead voluntarily withdrew the drug for the accelerated approval indication. Evaluate the regulatory oversight of the accelerated approval pathway and evidence generation for idelalisib during premarketing (2008-2014), postmarketing (2014-2016), and premarketing withdrawal periods (2016-2022). ClinicalTrials.gov, FDA.gov, PubMed database. Clinical trials investigating the safety and effectiveness of idelalisib. Study characteristics and relative risk (RR) of safety outcomes were abstracted. Data were pooled using random effects meta-analysis. The analysis was performed in October of 2022. Trial status, recruitment status, publication status, serious adverse events (SAEs), fatal adverse events (FAEs), and all-cause mortality. Overall, 31 idelalisib trials met selection criteria. In total, 20 of 30 (65%) included SLL and/or FL; 13 (42%) trials were completed, 13 (42%) had published results, and 7 (23%) were randomized clinical trials (RCTs). Overall, 6 RCTs of idelalisib had publicly available data on safety outcomes. By the initial postmarketing period (2016), the cumulative RR for SAEs was 1.86 (95% CI, 1.63-2.11), for FAEs was 3.30 (95% CI, 1.56-7.00), and for death was 1.35 (95% CI, 0.85-2.12). In the premarketing withdrawal period, only a single phase 3 trial was enrolling patients for FL and was terminated. However, idelalisib was not withdrawn from the market until 2022. Gilead reported cumulative sales revenue of $842 million during market authorization (2014-2022) and annual sales had a steady decline from $168 million to $62 million during the premarketing withdrawal period (2016-2021). Findings of this systematic review and meta-analysis show that serious risks of SAE, FAE, and death with idelalisib treatment were evident by 2016. However, idelalisib remained on the market for another 6 years, with minimal evidence generation. It was voluntarily withdrawn for FL and SLL accelerated approval indications coinciding with decreasing revenue generation. Closer attention for safety and effectiveness of drugs reaching market by accelerated approval is needed.

Effectiveness and safety of monoclonal antibodies against amyloid-beta vis-à-vis placebo in mild or moderate Alzheimer's disease.

Currently, no consensus has been reached on the therapeutic implications of monoclonal antibodies against amyloid-beta (Aβ) in Alzheimer's disease (AD). This study aimed to examine the effectiveness and safety of monoclonal antibodies against Aβ as a whole and also to determine the superiority of individual antibodies vis-à-vis placebo in mild or moderate AD. Literature retrieval, article selection, and data abstraction were performed independently and in duplicate. Cognition and function were appraised by the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Disability Assessment for Dementia (DAD), and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Effect sizes are expressed as standardized mean difference (SMD) with a 95% confidence interval (CI). Twenty-nine articles involving 108 drug-specific trials and 21,383 participants were eligible for synthesis. Of the four assessment scales, only CDR-SB was significantly reduced after using monoclonal antibodies against Aβ relative to placebo (SMD: -0.12; 95% CI: -0.2 to -0.03; p = 0.008). Egger's tests indicated a low likelihood of publication bias. At individual levels, bapineuzumab was associated with a significant increase in MMSE (SMD: 0.588; 95% CI: 0.226-0.95) and DAD (SMD: 0.919; 95% CI: 0.105-1.943), and a significant decrease in CDR-SB (SMD: -0.15; 95% CI: -0.282-0.018). Bapineuzumab can increase the significant risk of serious adverse events (OR: 1.281; 95% CI: 1.075-1.525). Our findings indicate that monoclonal antibodies against Aβ can effectively improve instrumental activities of daily life in mild or moderate AD. In particular, bapineuzumab can improve cognition and function, as well as activities of daily life, and meanwhile, it triggers serious adverse events.

The Efficacy and Safety of Subcutaneous Ixekizumab for the Treatment of Axial Spondylarthritis: A Systematic Review and Meta-Analysis.

Axial spondylarthritis (axSpA) is a progressive inflammatory condition that is treated with various management options. Interleukin-17A (IL-17A)inhibitors are a novel therapeutic option that demonstrates both efficacy and safety. This systematic review and meta-analysis evaluated the effectiveness of ixekizumab and its safety compared to a placebo. Medline, ScienceDirect, EBSCO, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched. We included randomized control trials (RCTs) that assessed the efficacy and safety of ixekizumab versus the placebo. The GRADE (Gradingof Recommendations, Assessment, Development, and Evaluations) assessment was utilized to evaluate the certainty of evidence. The revised Cochrane risk of bias tool for randomized trials was used to assess the risk of bias. Four RCTs (n=1016) met the eligibility criteria. All included studies had a low risk of bias. Significant improvements in the Assessment of Spondylarthritis International Society response for 40% improvement (ASAS40) (RR = 2.39, 95% CI 1.72-3.31, P < 0.01, I2 = 23%), Ankylosing Spondylitis Disease Activity Score (ASDAS) (SMD= -9.28 95% CI -12.31- (-6.25), P < 0.01, I2=97%), andSpondylarthritis Research Consortium of Canada (SPRACC score) (SMD= -5.82 95% CI -7.16- (-4.47), P < 0.01, I2=94%) were noted in comparison to placebo. Regarding safety, there was an insignificant increase in risk for serious adverse events (SAEs) (RR = 1.19, 95% CI 0.45-3.14, P = 0.73, I2 = 0%). Additionally, significant nonserious adverse events (NSAEs) (RR = 1.54, 95% CI 1.19-1.99, P = 0.001, I2 = 0%) were noted for the ixekizumab arm. No mortality events were detected in both arms. Ixekizumab, which demonstrates significant improvement in all efficacy endpoints, is a promising management option for axSpA patients who fail non-steroidal anti-inflammatory drugs (NSAIDs) therapy. However, the significant risk of developing adverse events hinders its utilization. More high-quality RCTs with larger sample sizes and prolonged follow-up periods are warranted to further assess this treatment option.

Tranexamic acid for the reduction of bleeding during functional endoscopic sinus surgery.

Tranexamic acid for the reduction of bleeding during functional endoscopic sinus surgery.

Physician preferences for nonmetastatic castration-resistant prostate cancer treatments: A discrete choice experiment among men in mainland China.

88 Background: A range of medication options are available for non-metastatic castration-resistant prostate cancer (nmCRPC), with varying efficacy and safety profiles. We used a discrete choice experiment (DCE) to explore how physicians make treatment decisions between adverse events (AEs) and survival gains in nmCRPC in mainland China. Methods: Physicians’ preferences for medication attributes were assessed through an online survey including 14 treatment choice questions, each comparing 2 hypothetical treatment profiles, which varied safety (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency and efficacy (overall survival [OS] and time to pain progression [TPP]) in terms of duration of effect. Preference weights and importance scores for each attribute were estimated using random parameters logit models. The amount of survival gain physicians were willing to trade off for a reduction in specific AEs was also estimated. Results: In total, 80 physicians who had experience in treating nmCRPC patients were involved in this study. Physicians’ duration of clinical practice was about 18.4±7.39 years. In addition, 57.6% of participants were from regions with more developed economics, including North, East and South China. The results indicated that physician preferences were logically ordered, with higher efficacy and lower risks for AEs being favored over lower efficacy and higher risks for AEs. The most important attributes for treatment decision were OS (Relative importance, RI = 29.2%), serious fracture (RI = 24.4%), serious fall (RI =15.4%) and TPP (RI =10.6%). Comparing non-serious AEs including fatigue, skin rash and cognitive problems, physicians emphasized the risk reduction of fatigue the most. The trade-off analysis between OS and adverse events suggested that physicians were willing to trade 7.5 and 4.7 months of OS to reduce the risk of severe fracture from 8% to none, and the risk of serious fall from 8% to none. In an exploratory subgroup analysis, it was found that physicians with more than 15 years of clinical practice put more emphasis on overall survival, risk of serious fracture, and risk of serious fall compared to less experienced physicians (≤15 years). Physicians from regions with more developed economics tended to put more value on reduction of AEs as compared to physicians from the rest regions. Conclusions: OS is the most important attribute for physicians when treating nmCRPC patients. Physicians were willing to trade the duration of OS to reduce the risk of serious adverse events. These results emphasize the importance of carefully balancing therapies’ benefits and risks to ultimately optimize the overall quality of nmCRPC patients’ survival.