Pathways to Employee Outcomes in a Workplace Health Promotion Program

Purpose This study examined the relationship between employee outcomes and employer implementation of evidence-based interventions (EBIs) for chronic disease prevention. Design Cross-sectional samples collected at 3 time points in a cluster-randomized, controlled trial of a workplace health promotion program to promote 12 EBIs. Setting King County, WA. Sample Employees of 63 small, low-wage workplaces. Measures Employer EBI implementation; 3 types of employee outcomes: perceived implementation of EBIs; perceived employer support for health; and health-related behaviors, perceived stress, depression risk, and presenteeism. Analysis Intent-to-treat and correlation analyses using generalized estimating equations. We tested bivariate associations along potential paths from EBI implementation, through perceived EBI implementation and perceived support for health, to several employee health-related outcomes. Results The intent-to-treat analysis found similar employee health-related behaviors in intervention and control workplaces at 15 and 24 months. Workplaces implemented varying combinations of EBIs, however, and bivariate associations were significant for 4 of the 6 indicators of physical activity and healthy eating, as well as perceived stress, depression risk, and presenteeism. We did not find significant positive associations for cancer screening and tobacco cessation. Conclusion Our findings support broader dissemination of EBIs for physical activity and healthy eating, as well as more focus on improving employer support for employee health. They also suggest we need better interventions for cancer screening and tobacco cessation.

Evidence-Based Therapist-Supported Digital Mental Health Intervention for Patients Experiencing Medical Multimorbidity: A Retrospective Cohort Intent-to-Treat Study

Objective: Multimorbidity or the co-occurrence of multiple health conditions is increasing globally and associated with significant psychological complications. It is unclear whether digital mental health (DMH) interventions for patients experiencing medical multimorbidity (MMB) are effective, particularly given that this patient population faces more treatment resistance. Therefore, there is a need for initial preliminary research to examine whether DMH interventions are associated with reductions on depressive and anxiety symptoms in the context of MMB.Methods: This preregistered retrospective cohort intent-to-treat study with 2,819 patients enrolled in a therapist-supported DMH (TS-DMH) intervention examined the associations between MMB and mental health. Results: Results indicated that more MMB was significantly associated with greater presenting mental health symptom severity. MMB did not have a deleterious influence on depressive symptom trajectories across treatment, although having one medical condition was associated with a steeper decrease in anxiety symptoms compared to patients with no medical conditions. Finally, MMB was not associated with time to dropout, but was associated with higher dropout and was differentially associated with fewer beneficial treatment outcomes, although this is likely attributable to higher presenting symptom severity, rather than lesser symptom reductions during treatment. Conclusions: The MHP showed preliminary effectiveness as an evidence-based treatment for patients experiencing depression and anxiety in the context of MMB. Future DMH treatments and research might investigate tailored barrier reduction and extended treatment lengths for patients experiencing MMB to allow for greater treatment dose to reduce symptoms below clinical outcome thresholds.

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report

PURPOSE Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration–approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel. METHODS We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity. RESULTS Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively. CONCLUSION Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study

Background In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan. Methods Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints. Results The Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred. Conclusions Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.

1433. Impact of 2019 US Food and Drug Administration (FDA) Guidance on Developing Drugs for Urinary Tract Infection (UTI) on the Perceived Efficacy of Antibiotics for the Treatment of Uncomplicated UTI (uUTI)

Background In 2019, the FDA issued guidance on drug development for treatment of UTIs. To explore the impact of this guidance, we compared clinical and microbiological outcomes of the fluoroquinolones norfloxacin and ciprofloxacin and the β-lactams pivmecillinam and sulopenem for treatment of uUTIs from original publications versus recent analyses conducted in accordance with the FDA guidance. Methods The efficacy of pivmecillinam 400 mg twice daily (BID), 3 days (3d) versus norfloxacin 400 mg BID, 3d was reported in a 2002 publication. Patient-level data were used to re-analyze clinical and microbiological outcomes in the microbiological intent-to-treat population in accordance with the 2019 FDA guidance. For descriptive comparison, we present the efficacy of ciprofloxacin 250 mg BID, 3d vs sulopenem 500 mg BID, 5d in the 2020 SURE-1 trial (also conducted in accordance with FDA guidance) alongside historical efficacy data for ciprofloxacin. Results Re-analysis of data from the trial of pivmecillinam and norfloxacin showed microbiological responses for pivmecillinam and norfloxacin of 64% and 79%, respectively. Microbiological responses were higher, 75% for pivmecillinam and 91% for norfloxacin, in the original analysis. For clinical response, re-analysis showed 75% for pivmecillinam and 88% for norfloxacin, while historical data were 82% and 88%, respectively. In the SURE-1 trial, the microbiological response of patients assessed at Day 12 was 76.6% for sulopenem and 79.1% for ciprofloxacin. In a 2002 publication, bacterial eradication at 4 to 11 days after treatment was 93.7% for ciprofloxacin 250 mg, a higher response rate than that reported in SURE-1. For clinical response, rates were 78.7% for ciprofloxacin in SURE-1 and 92.7% for the historical ciprofloxacin data. Conclusion When assessed in accordance with the 2019 FDA guidance, clinical and microbiological efficacy of both fluoroquinolones and β-lactam antibiotics appears lower than has been published in the past. Healthcare providers should be aware that newer antibiotics may appear to have a lower efficacy than older antibiotics due to the application of more stringent definitions in the FDA guidance. Disclosures Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant) Lindsay Nicolle, MD, Entos (Consultant)GSK (Consultant)Iterum (Consultant)Utility Therapeutics (Consultant) Anita F. Das, PhD, Adagio Therapeutics, Inc. (Consultant)

Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence

BackgroundMost patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.MethodsPatients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients.ResultsFor randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)).ConclusionsSeviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas.Trial registration numberNCT01546571.

Coaches Activating Reaching and Engaging Patients (CAREPlan): A randomized controlled trial combining two evidence-based interventions to improve goals of care documentation.

2 Background: In our prior work, community or lay health worker-led goals of care interventions improved goals of care documentation by clinicians and decreased health care use at the end of life. Other studies have demonstrated improvements in provider-patient communication and goals of care documentation using the Serious Illness Care Program. The objective of this study was to determine whether the combination of these two interventions could improve goals of care documentation among patients with advanced stages of genitourinary cancers at an academic center. Methods: A randomized controlled trial was conducted from April 3, 2019, through October 30, 2019, among patients with metastatic or recurrent cancer on at least second line therapy in the urologic oncology clinics at Stanford Cancer Center. Patients were randomized to usual care or the intervention with a lay navigator trained to assist patients with establishing end-of-life care preferences using the Serious Illness Conversation Guide. The primary outcome was goals of care documentation by the primary oncologist. We used intent to treat analyses, descriptive statistics to compare demographic and clinical factors, and a logistic regression adjusting for imbalance to determine the effect on the primary outcome. Results: Two-hundred participants were randomized and included in the intent to treat analysis. Median age was 72 years, majority were male (n=175, 87.5%) and self-identified as non-Hispanic white (n=123, 61.5%). The majority had prostate cancer (n=110, 53.5%), followed by kidney cancer (n=51, 25.5%), and urothelial cancer (n=29, 14.5%) and most had stage IV disease at diagnosis (n=186, 93%). There were no significant differences in demographic or clinical factors except for gender; there were more females on the control arm (n=8 vs n=17, p=0.01) thus analysis of the primary outcome was adjusted for gender. The adjusted analysis showed that at 12 months post-enrollment, the intervention significantly increased goals of care documentation by the primary oncologist as compared to the control group (53.7% vs 32.6%, p=0.002). Conclusions: The CAREPlan program increased goals of care documentation by the primary oncologist at this single academic medical center. Clinical trial information: NCT03856463.

Covid-19 in the Phase 3 Trial of mRNA-1273 During the Delta-variant Surge

BackgroundFollowing emergency use authorization in December 2020, the Coronavirus Efficacy (COVE) trial was amended to an open-label phase, where participants were unblinded and those randomized to placebo were offered vaccination. Emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with increased incidences of coronavirus disease 2019 (Covid-19) among unvaccinated and vaccinated persons. This exploratory analysis evaluated the incidence and genetic sequences of Covid-19 cases in the ongoing COVE trial during the open-label phase, with a focus on July-August 2021, when delta-variants surged in the US.MethodsCovid-19 cases were identified in participants initially randomized to mRNA-1273 (vaccinated from July-December 2020) and those initially randomized to the placebo (vaccinated December 2020-April 2021) who received at least one dose and were SARS-CoV-2-negative at baseline in the modified-intent-to-treat population were analyzed. Included were Covid-19 cases occurring after 26-Mar-2021 with positive RT-PCR results in nasopharyngeal samples (central lab test) and reported Covid-19 symptoms. Genetic sequencing of Covid-19 cases was also performed.ResultsThere were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA1273 (mRNA-1273p) group. Covid-19 cases increased from the start of the open-label phase to July-August 2021. During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group. Of the cases sequenced, 144/149 [97%]) in the mRNA-1273 and 86/88 (99%) in the mRNA-1273p groups were attributed to delta. The incidence rate of Covid-19 was lower for the mRNA-1273p (49.0/1000 person-years) versus mRNA-1273e (77.1/1000 person-years) group [36.4% (95% CI 17.1%-51.5%) reduction]. There were fewer severe Covid-19 cases in the mRNA-1273p (6; 6.2/1000 person-years) than mRNA-1273e (13; 3.3/1000 person-years) [46.0% (95% CI −52.4%-83.2%) reduction]. Three Covid-19 related hospitalizations occurred with two resulting deaths in the mRNA-1273e group.ConclusionIncidence rates of Covid-19 and severe Covid-19 were lower during the months when delta was the dominant variant (July/August 2021) among COVE participants vaccinated more recently. Analysis of COVID-19 cases from the open-label phase of the COVE study is ongoing.