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Background Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI. Methods In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs. Results Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: −4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: −14.1%, −4.5%; P =.0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome. Conclusions Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration. Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566. [ABSTRACT FROM AUTHOR]

Background Few therapies are approved for hospitalized patients with severe coronavirus disease 2019 (COVID-19). Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, may mitigate COVID-19–induced lung damage by reducing inflammatory cytokines. The multicenter, randomized, double-blind phase 2 iNSPIRE study evaluated ibrutinib for prevention of respiratory failure in hospitalized patients with severe COVID-19. Methods Adult patients with severe COVID-19 requiring hospitalization and supplemental oxygen but without respiratory failure were randomized 1:1 (stratified by remdesivir prescription) to ibrutinib 420 mg or placebo once daily for up to 28 days plus standard of care (SOC), including remdesivir and/or dexamethasone. Results Forty-six patients were randomized to ibrutinib plus SOC (n = 22) or placebo plus SOC (n = 24). The primary endpoint (proportion of patients alive and without respiratory failure through day 28) was not met, with no statistically significant difference adjusting for remdesivir prescription (86% with ibrutinib plus SOC vs 79% with placebo plus SOC; adjusted difference, 5.8% [80% confidence interval, –9.2% to 20.4%]; P  = .599). Secondary endpoints also showed no statistically significant improvement with ibrutinib plus SOC. Median treatment duration was 14 days for ibrutinib and placebo. Adverse events were similar with ibrutinib plus SOC vs placebo plus SOC (overall: 55% vs 50%; serious: 18% vs 13%) and were consistent with the known safety profile of ibrutinib. Conclusions Addition of ibrutinib to SOC did not improve the proportion of patients alive and without respiratory failure through day 28 in hospitalized patients with severe COVID-19. Ibrutinib had a manageable safety profile, with similar safety to placebo. Clinical Trials Registration NCT04375397. [ABSTRACT FROM AUTHOR]

Sickle cell anaemia ( SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites ( NOx), high sensitivity C-reactive protein (hs- CRP), vascular cell adhesion molecule 1 ( VCAM-1), intercellular adhesion molecule 1 ( ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor ( VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain ( P = 0·0003), oral analgesic use ( P = 0·003) and circulating hs- CRP ( P = 0·003), soluble (s)E-selectin ( P = 0·01), sICAM-1 ( P = 0·02), sICAM-3 ( P = 0·02) and sVEGF ( P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide ( HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA. [ABSTRACT FROM AUTHOR]

Background: Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease. Methods: We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions. Results: The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied. Conclusions: GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM), leukocyte activation (MAC-1, LFA-1, PM aggregates) and the coagulation cascade (tissue factor, thrombin-antithrombin complexes). Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing. Trial Registration: ClinicalTrials.gov NCT00911495 [ABSTRACT FROM AUTHOR]

Acute chest syndrome ( ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease ( SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 ( sPLA2). In a feasibility study ( PROACTIVE; NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial. [ABSTRACT FROM AUTHOR]

Advances in molecular diagnostics have led to an increased interest in expanding population-based screening to include genetic diseases that occur outside the newborn period. Hereditary hemochromatosis may be a candidate for large-scale screening in populations with a high prevalence of the common HFE mutations. To determine race-specific frequencies of the HFE mutations, C282Y and H63D, the authors applied an automated, high-throughput genotyping method to dried blood spot samples from a representative population of California newborns. In this sample of 3989 newborns, C282Y and H63D allele frequencies were highest in white (C282Y: 5.5 ± 0.5%; H63D: 13.4 ± 0.76%) and Hispanic (C282Y: 1.8 ± 0.29%; H63D: 11.9 ± 0.72%) newborns, and lowest in black (C282Y: 1.3 ± 0.25%; H63D: 3.0 ± 0.38%) and Asian (C282Y 0.5 ± 0.16%; H63D 2.9 ± 0.37%) newborns. The estimated prevalence of C282Y homozygotes in this multiracial population is 1.4/1000. As additional genetic and environmental risk factors for HHC are identified, neonatal screening may become an acceptable strategy to follow susceptible individuals and prevent clinical disease. [ABSTRACT FROM AUTHOR]

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton tyrosine kinase, is approved in the US for CLL/SLL treatment, including in combination with obinutuzumab. The combination of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab was investigated in patients with previously untreated CLL in an international, randomized phase 3 study, iLLUMINATE (PCYC-1130; NCT02264574). Objectives: To educate on nursing practices for monitoring adverse events (AEs) and providing patient education when treating with ibrutinib. Methods: Eligible patients had previously untreated CLL/SLL requiring treatment and were aged ≥65 years or <65 years with coexisting conditions. Patients were randomized (1:1) to receive ibrutinib (420 mg once daily continuously) plus 6 cycles of obinutuzumab infusion (1000 mg on days 1/2, 8, and 15 of cycle 1; day 1 of cycles 2-6), or 6 cycles of oral chlorambucil plus obinutuzumab. Results: Among 229 randomized patients, median age was 71 years (range, 40-87), with Cumulative Illness Rating Scale score >6 in 32% and baseline cytopenia in 55%; 65% had high-risk genomic features defined as del(17p), del(11q), TP53 mutation, or unmutated IGHV. With median follow-up of 31.3 months, progression- free survival was significantly prolonged for patients on ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab (median not reached [NR] vs 19.0 months), including in the high-risk population (median NR vs 14.7 months). Overall response rates were 88% with ibrutinib-obinutuzumab and 73% with chlorambucil- obinutuzumab; complete response (with/without bone marrow recovery) rates were 19% versus 8%. In patients with baseline thrombocytopenia, sustained improvement in platelet counts during the first 6 months of therapy occurred in 32% on ibrutinib-obinutuzumab and 27% on chlorambucil-obinutuzumab; in patients with anemia, improvement in hemoglobin occurred in 51% and 42%, respectively. Nurses provided symptoms-based education on hematologic improvements and how that impacted patient health, which was important for educating patients on the benefits of continuing therapy. With up to 3 years follow-up, 70% of ibrutinib-obinutuzumab patients remained on single-agent ibrutinib therapy. Most common reasons for ibrutinib discontinuation included AEs (16%) and progression (4%). Median treatment duration was 29.3 months with ibrutinib-obinutuzumab and 5.1 months with chlorambucil- obinutuzumab. Infusion-related reactions (IRRs) with obinutuzumab occurred less frequently with ibrutinib-obinutuzumab than chlorambucil-obinutuzumab (any grade, 25% vs 58%; grade ≥3 or serious, 3% vs 9%); no patients discontinued obinutuzumab infusions due to IRR with ibrutinib-obinutuzumab, versus 7 (6%) for chlorambucil-obinutuzumab. Nurses have key roles in discussing AE recognition and management with patients, including explaining IRR management plans (eg, medications to help prevent and treat IRRs) to ease patients' anxiety. During infusions, nurses monitored patients closely to detect any early signs/symptoms of IRR. Other common AEs (>25%) with ibrutinib-obinutuzumab were neutropenia (43%), thrombocytopenia (35%), diarrhea (34%), and cough (27%). Nurses monitored for cytopenias and infection risk with regular evaluation of blood counts, and educated patients on signs/symptoms of fever and infection. Conclusion: First-line combination therapy with ibrutinib-obinutuzumab represents an effective chemotherapy- free regimen for patients with CLL and is associated with significantly improved PFS and fewer IRRs versus chlorambucil- obinutuzumab. Oncology nurses play critical roles in educating patients, monitoring AEs, and supporting the management of patients receiving continuous ibrutinib therapy to help achieve maximal treatment benefit. Sponsor: Pharmacyclics LLC, an AbbVie Company. [ABSTRACT FROM AUTHOR]

Objectives: Disease symptoms and treatment complications can profoundly affect quality of life (QOL) in patients (pts) with chronic lymphocytic leukemia (CLL). Ibrutinib (ibr), a B-cell receptor pathway inhibitor, improved QOL in pts with relapsed/refractory CLL. Frontline ibr versus chlorambucil (clb) has also shown impressive single-agent efficacy and acceptable safety in a randomized phase 3 study (RESONATE-2) in older CLL pts; ibr reduced the risk of progression or death by 91% and the risk of death by 84% versus clb. Here, we compare the QOL and hematologic function of patients treated with frontline ibr versus clb. Methods: In RESONATE-2, patients aged e65 years were randomized to ibr (420 mg [3 capsules] once daily until disease progression [n = 136]), or clb (0.5-0.8 mg/kg on days 1-15 of 28-day cycles for up to 12 cycles [n = 133]). Well-being was evaluated by measuring improvements in patient-reported outcomes (FACIT-Fatigue and EORTC-QLQ-C30), hematologic function, and disease symptoms. Results: Overall response rate for ibr was 86% versus 35% with clb. Patients treated with ibr versus clb reported greater improvements in fatigue (P = .0004) and global health status (P = .0002). Sustained improvement in hematologic function occurred in 84% of ibr-treated patients with baseline anemia and 77% with baseline thrombocytopenia versus 45% and 43%, respectively, with clb. Median time to first sustained improvements in hemoglobin and platelet counts occurred 8 months earlier with ibr than with clb. Disease symptoms (fatigue, night sweats, and weight loss) improved more frequently with ibr versus clb. The most frequent adverse events (AEs) with ibr included diarrhea, fatigue, cough, and nausea and were largely mild (grade 1) versus clb, which included nausea, fatigue, neutropenia, anemia, and vomiting. Grade e3 AEs with ibr were most common in the first 6 months and generally decreased over time. AEs leading to discontinuation or dose reduction of ibr were infrequent, and 87% of patients were continuing ibr at end of the study. Conclusion: Ibr improves QOL and hematologic function while prolonging survival. It is critical that nurse navigators educate their ibr patients about the potential improvement in survival and efficacy that they are likely to experience. Because most AEs are grade 1 and manageable, nurse navigators should provide guidance on symptom intervention and management to ensure that patients are able to adhere to their ibr regimen. Patients should also be informed about the importance of continuing ibr at the recommended, once-daily dose to maximize the likelihood of benefit. Sponsor: Pharmacyclics LLC, and AbbVie Company. [ABSTRACT FROM AUTHOR]