Citations

Abstract The substantial carbon footprint imparted by medical services warrants increased attention to their environmental impact. National guideline organizations such as the US Preventive Services Task Force (USPSTF) recommend multiple modalities for average-risk colorectal cancer (CRC) screening with varying resource intensity. The aim of this study was to quantify the environmental burden for 2 of the most used CRC screening modalities, colonoscopy and the multi-target stool DNA (mt-sDNA) test. A validated CRC microsimulation model was used to estimate the number of screening and follow-up tests for a cohort of 1 million average-risk individuals who underwent screening between ages 45 and 75. Component resources used for mt-sDNA, including waste products, energy, and transportation for colonoscopy and mt-sDNA, were collected from January 1, 2023, to January 1, 2024, and converted to carbon-equivalent emissions. Resources used for colonoscopy were captured from the literature. Resources devoted to screening colonoscopy were substantially (59%) higher than those to mt-sDNA, even when including follow-up colonoscopy. Of note, follow-up colonoscopy accounted for the majority (64%) of total emissions for the mt-sDNA screening strategy. Compared with colonoscopy screening, mt-sDNA substantially reduces the carbon emissions attributable to population-level CRC screening. Environmental impact should be included as a factor when choosing among guideline-recommended CRC screening strategies.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Abstract Background Antibiograms are an important stewardship tool that can inform optimal empiric therapy; most antibiograms are hospital-wide. Unit-specific antibiogram data for unique patient populations including intensive care unit and pediatrics is robust; however, published experience with unit-specific antibiograms in the hematology-oncology (heme-onc) population is limited. These patients are unique because of the common use of antimicrobial prophylaxis, prolonged broad-spectrum antibiotics, and an immunocompromised state. We sought to examine the trends in antibiogram antimicrobial susceptibility over time. Methods This retrospective quality initiative included microbiology results (first isolates per patient per timeframe) from Mayo Clinic Rochester from 2012 to 2022. Eligible cultures were those identified as being obtained from one of 8 hematology, oncology, or bone marrow transplant inpatient units. Agar dilution susceptibility testing and Clinical and Laboratory Standards Institute (CLSI) breakpoints were used. Screening PCRs (eg, VRE PCR) were excluded. Culture and susceptibilities were identified by an EMR based report, compiled annually, and reported for two-year periods. Susceptibility rates were compared using the Chi-square test and Chi-square analysis for trends. Results There were 4 gram-negative and 5 gram-positive organism groups that met CLSI antibiogram criteria of ≥ 30 isolates and were included (tables 1-4). There were several significant differences in comparison to the hospital-wide antibiogram, with lower antibiotic susceptibility rates in the heme-onc units for multiple organisms, notably fluoroquinolones to E.coli and P. aeruginosa and several cephalosporins to Enterobacterales as well as penicillin and levofloxacin to Viridans group Streptococcus and vancomycin to E. faecium (tables 1&2). Over the period of 2012-2013 to 2021-2022, susceptibility rates remained stable among the heme-onc antibiogram, with few significant changes (tables 3&4). Conclusion Heme-onc antibiograms illustrated susceptibility rate differences compared to our hospital-wide antibiograms, particularly for antimicrobials used as prophylaxis. Through population-specific antibiograms, providers may be able to improve empiric antibiotic selection. Disclosures Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member

89 Background: With estimates of over 150,000 incident and 50,000 fatal colorectal cancer (CRC) cases in 2024, efforts are ongoing to improve the national screening performance and engagement in the US. The Centers for Medicare & Medicaid Services (CMS) have established criteria for covering new blood-based CRC screening tests if minimum CRC sensitivity and specificity thresholds are met. However, the current blood-based tests are challenged by their relative inability to detect advanced precancerous lesions (APLs). At present, the importance of APL versus CRC sensitivity on screening outcomes remains undetermined. To address this knowledge gap, we conducted a simulation study to compare the screening effectiveness and outcomes of a hypothetical blood-based test across a range of sensitivities for CRC and APL detection. Methods: Outcomes were simulated using the CRC-AIM microsimulation model, which has been previously calibrated and validated. Predicted outcomes were calculated for average-risk individuals screened triennially with a blood-based test between ages 45-75 years, assuming perfect adherence. Base-case screening sensitivity and specificity inputs were based on CMS minimum thresholds (74% CRC sensitivity, 90% specificity) with assumed 10% APL sensitivity. Additional scenarios considered an increase in either APL or CRC sensitivity. Outcomes of interest included life years-gained (LYG), CRC incidence, and mortality reductions. Results: Compared to the CMS minimum performance (Table), increasing APL sensitivity by 1% (from 10% to 11%) resulted in a similar increase in LYG as compared to increasing CRC sensitivity by 11% (from 74% to 85%). Additionally, increasing APL sensitivity by 1% resulted in greater reductions in CRC cases and deaths (3% decrease) as compared to increasing CRC sensitivity by 11% (0% and 1% reductions, respectively). Conclusions: Data from this study show that increased APL sensitivity is a key determinant of screening-related outcomes, such as LYG, derived from a blood-based strategy, and that similar results would require much larger increases in CRC sensitivity. With the current CMS minimum performance threshold, blood-based tests that are designed to have high APL sensitivity can outperform tests with higher CRC sensitivity and little to no APL sensitivity. Comparison of CRC screening health outcomes with CMS proposed minimum threshold blood-test versus hypothetical tests with either increased APL and CRC sensitivity. APL Sensitivity CRC Sensitivity CRC Specificity Follow-up Colonoscopies CRC Cases (% reduction) CRC Deaths (% reduction) Life-Years Gained (LYG) (% increase) 10% 74% 90% 809 50 (ref) 18 (ref) 220 (ref) 11% 74% 90% 813 48 (-3%) 17 (-3%) 226 (3%) 10% 85% 90% 809 50 (0%) 18 (-1%) 227 (3%) APL: Advanced precancerous lesions; CRC: Colorectal cancer.

88 Background: There are an estimated 60 million individuals in the US who are not up-to-date with average-risk colorectal cancer (CRC) screening, as screening rates and adherence have remained stubbornly below the national target of 80%. Efforts are ongoing to improve CRC screening performance and participation, including the development of new blood-based tests. Despite high expectations for these tests, performance remains lower than other guideline-recommended strategies, particularly with respect to advanced precancerous lesion (APL) sensitivity. We conducted a simulation study of estimated clinical and economical outcomes for CRC screening with a blood-based test (at perfect adherence) compared to the multi-target stool-DNA (mt-sDNA) test (at published adherence rates). Methods: Utilizing CRC-AIM, a calibrated and validated microsimulation model, CRC screening outcomes were calculated for 1 million average-risk individuals screened between ages 45-75 years with triennial blood-based versus mt-sDNA testing. CRC and APL sensitivity and specificity inputs were derived from two large clinical validation studies for these screening modalities: ECLIPSE (NCT04136002) and DeeP-C (NCT01397747), respectively. To demonstrate the maximum benefits and burdens of blood-based screening, adherence to initial screening and follow-up colonoscopy after a positive blood test was modeled at 100%, while real-world adherence estimates of 65.6% were used for the mt-sDNA test. Outcomes of interest included life years-gained (LYG) and CRC cases missed by the blood-based test compared to the stool-based test, additional treatment costs imposed by theblood-based test, and additional CRC-related deaths per 1 million screened. Results: Compared to triennial screening with mt-sDNA at real-world adherence, blood-based screening at perfect adherence resulted in a higher number of incident (n=18,464) and fatal (n=6,483) CRC cases that would been avoided with the mt-sDNA test. Over a lifetime, screening with blood-based tests required 1,276,310 more tests (21% more) and 52,942 additional follow-up colonoscopies (7% more) compared to mt-sDNA screening. This increased testing burden did not generate additional benefits and instead reduced life-years gained by 67,645 per 1 million screened, resulting in an additional $1.6 billion in treatment costs compared to the mt-sDNA strategy. Conclusions: Data from this CRC-AIM modeling study show that even with perfect adherence, blood-based screening yields inferior clinical and economic benefits compared to mt-sDNA screening, due to suboptimal APL detection with the former test.