Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design.

BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. DISCUSSION: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.

Changes in Personal Protective Equipment Practices of Craniofacial Surgeons during COVID-19: A Cross-sectional Study.

Surgeons who operate around nasal or oral airways are at particularly high risk for transmission of the severe acute respiratory syndrome coronavirus 2. This multipart study explores the changes in craniofacial surgeon preferences and practices for personal protective equipment (PPE) over the course of a worldwide pandemic. Methods: Two identical electronic survey studies, one in 2020 and one in 2022, were conducted on the use of PPE before, during, and after the pandemic among active craniomaxillofacial surgeons. Statistical changes in behaviors and preferences and differences across time points and demographic groups were evaluated. Results: The initial study included responses from 48 surgeons, and the follow-up study consisted of 36 responses. Although only 4.3% of surgeons wore N95 masks or powered air purifying respirator for craniomaxillofacial operations before the pandemic, 91.5% wore these measures during the early pandemic (P < 0.001). However, this fell to 74.3% 2 years later. Similarly, more than 95% of surgeons wore a mask in clinic during the pandemic at both time points compared to only 40.3% before the pandemic (P < 0.001). In 2020, 31.9% of surgeons planned to continue using N95 masks or powered air purifying respirator for craniofacial cases after the pandemic was over, but that fell to 11.4% in the follow-up study. Conclusions: Craniofacial surgeon practices have shifted significantly toward more protective PPE over the course of the coronavirus disease 2019 pandemic. However, this effect was dampened over the course of a protracted pandemic. Despite this, our studies indicate a long-term shift in surgeon preference that is likely to persist after the pandemic is over.

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

The Impact of COVID-19 on the Personal Protective Equipment Practices and Preferences of Craniofacial Surgeons.

BACKGROUND: The COVID-19 pandemic has raised concern about healthcare worker exposure risk. Surgeons operating near the aerodigestive tract are at particularly high risk, given the respiratory spread of SARS-CoV-2. This study examines the practices and opinions of craniofacial surgeons as they adapt to a worldwide epidemic. METHODS: An electronic survey study was conducted on practicing craniomaxillofacial surgeons regarding their preference of personal protective equipment use before, during, and after the pandemic in patients with or without COVID-19 infection, as well as demographic data. Statistical analysis was performed to compare changes in behaviors and preferences and differences across demographic groups. RESULTS: Craniofacial surgeons changed their behaviors significantly during the pandemic, with 91.5% of respondents wearing N95 masks or powered air purifying respirators for operations involving exposure of the nasal or oral airways on untested patients, compared with 4.3% before the pandemic (P < 0.001). For examinations in the clinic, 100% reported wearing a mask during the pandemic compared with 40.3% before the pandemic (P < 0.001). After the pandemic is over, 31.9% of surgeons planned to continue using an N95 mask or powered air purifying respirator for craniomaxillofacial cases and 80.9% planned to continue using masks in clinic. Overall, 46.8% of respondents believed that N95 masks should be the standard for craniofacial surgery. CONCLUSIONS: The COVID-19 pandemic has significantly shifted the practices and opinion of craniofacial surgeons toward more protective personal protective equipment. These results indicate that this is likely to persist after the pandemic is over, which may limit surgeon exposure to airborne disease and help the field withstand future epidemic outbreaks.