Citations

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

AbstractAimAn estimated 5%–25% of women with endometriosis have colorectal involvement. Colorectal resection is the most suitable surgical management for cases with large bowel infiltration. However, this method is also associated with the highest rate of postoperative complications. Data focusing on surgeon speciality and surgical outcomes are currently limited. The aim of this work was to evaluate the surgical characteristics and short‐term postoperative outcomes following colorectal resection for endometriosis according to surgeon speciality.MethodUsing the National Surgical Quality Improvement Program (NSQIP) database, we included women who underwent colorectal resection for endometriosis between 2012 and 2020. Surgeries by general/colorectal surgeons were compared with those by gynaecological surgeons. The primary outcome was major complications according to the Clavien–Dindo classification.ResultsAmong 745 colorectal resections, 82.3% were performed by general/colorectal surgeons and 17.7% by gynaecologists. Racial and ethnic characteristics differed between groups, but other baseline characteristics were comparable. General/colorectal surgeons performed fewer minimally invasive surgeries (29.9% vs. 58.3%, p < 0.001). General/colorectal surgery cases had lower rates of any postoperative complications and minor complications (14.8% vs. 29.5%, p < 0.001; 10.1% vs. 23.5%, p < 0.001), while major complication rates were similar. Multivariable regression showed no association between major complications and surgical speciality. In a propensity score‐matched analysis, no significant differences were found between the two cohorts.ConclusionMost colorectal resections are performed by general/colorectal surgeons while a minimally invasive approach is more common among gynaecologists. There were no significant differences in outcomes between the two groups after adjusting for confounding variables. This suggests considering a multidisciplinary or dual surgery team approach to deep infiltrative endometriosis requiring bowel resection.

Abstract Background and Aims Patients with inflammatory bowel disease (IBD) face increased risk of colorectal cancer (CRC). While the natural history of conventional dysplastic precursor lesions has been well-studied, the neoplastic potential of recently described nonconventional (NC) IBD-associated colonic mucosal lesions is unclear. We aimed to assess the incidence of antecedent NC lesions in patients with IBD who developed CRC. Methods A case-cohort study was performed to include patients with a diagnosis of IBD with or without CRC who underwent at least 2 surveillance endoscopic procedures at our institution between 1/1/2007 and 5/31/2023. NC lesions included serrated change and indefinite for dysplasia. Detection rates pre- and post-introduction of high-definition (HD) surveillance colonoscopy were compared. Results In total, 87 patients with IBD and CRC and 200 patients with IBD without CRC were identified. Of the cases, a majority had ulcerative colitis (n = 52, 60%), most commonly with extensive involvement (n = 46, 89%). Conventional (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.34-3.52) and NC (HR 2.28, 95% CI 1.59-3.26) lesions were associated with increased risk of CRC. Conventional lesions in the post-HD era appeared to have a stronger association with CRC (HR 2.79, 95% CI 1.62-4.77) than NC lesions (HR 1.62, 95% CI 0.86-3.06). Conclusions Both conventional and NC lesions seem to be associated with increased risk of CRC. Conventional lesions are more strongly associated with CRC than NC lesions in the post-HD era, but misclassifications in the pre-HD era may have resulted in a biased increased risk estimate for NC lesions.

TPS309 Background: Patients with oligometastatic colorectal cancer (CRC) often experience long-term progression-free survival and overall survival (OS) following aggressive local treatment of isolated metastases, especially in the liver. However, the effectiveness of local ablative therapies, such as microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), in patients with inoperable limited metastatic CRC or those with additional metastases outside the liver or lungs, remains uncertain. Despite the historical use of local therapy for oligometastatic CRC, often influenced by provider bias rather than strong evidence, questions persist about the potential benefits of applying this approach to patients with more extensive disease. This trial aims to address this clinical challenge by evaluating the safety and efficacy of adding total ablative therapy (TAT) of all disease sites to standard systemic treatment in patients with limited metastatic CRC. Methods: A022101/NRG-GI009 is a randomized phase III study within the National Clinical Trials Network, set to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable). Patients with liver-only metastatic disease are excluded. Pre-registration during first-line systemic therapy induction is encouraged. Eligible lesions must be treatable with surgical resection, MWA, and/or SBRT. Patients without significant radiographic progression after 12-39 weeks of first-line systemic therapy, with 4 or fewer disease sites post-induction chemotherapy, will be randomized 1:1. Randomization will be stratified by the number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and the presence of metastatic disease outside the liver/lungs in at least one site. Patients in Arm 1 will receive TAT, targeting all metastatic sites with a combination of surgical resection, MWA, and/or SBRT, followed by standard systemic therapy. Patients in Arm 2 will continue with standard systemic therapy alone. The choice of systemic therapy is at the discretion of the medical oncologist and may include continued therapy, maintenance chemotherapy, or observation. The primary endpoint is OS, with secondary endpoints including event-free survival, treatment-related toxicities, and local recurrence. Exploratory biomarker analyses will also be conducted. The study requires 346 evaluable patients across the two arms to demonstrate an OS improvement with a hazard ratio of 0.7, providing 80% power with a one-sided alpha of 5%. The trial employs a group sequential design with two interim analyses (at 25% and 50% of events) to assess futility. The trial began in January 2023, and patient recruitment is ongoing. Clinical trial information: NCT05673148 .

Background: Reverse shoulder arthroplasty (RSA) is increasingly used in the treatment of proximal humerus fractures (PHFs) with reliable clinical improvement. Lateralized RSA implants have conferred superior outcomes compared with the original Grammont design in patients with nontraumatic indications. However, in the setting of a PHF, lateralized components can place increased tension across the tuberosity fracture site and potentially compromise tuberosity healing and outcomes. This systematic review and meta-analysis sought to determine the effect of implant design on clinical outcomes after RSA for PHFs. Methods: A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane were queried for clinical studies on RSA performed for PHFs that reported implant manufacturer details. Our primary outcomes included postoperative external rotation (ER), forward elevation (FE), abduction, Constant score, rate of greater tuberosity (GT) healing, and the incidence of complications compared between medialized vs. lateralized global implant design. Results: Globally lateralized RSA cohorts (478 RSAs total with cumulative lateral offset achieved through humeral or glenoid lateralization or both humeral and glenoid lateralization) were found to have a greater mean postoperative Constant score compared with globally medialized (medialized glenoid and medialized humerus) RSA cohorts with 1,494 total medialized RSAs (66 vs. 59, p = 0.006), but there was no significant difference regarding mean postoperative ER (30° vs. 22°, p = 0.078), FE (117° vs. 119°, p = 0.708), or abduction (103° vs. 107°, p = 0.377). On meta-regression, neither implant design nor tuberosity status significantly influenced postoperative ER, FE, abduction, or Constant score on meta-regression independent of mean follow-up and age at surgery. The rate of GT healing was greater in lateralized compared with medialized RSAs (88% vs. 72%, p < 0.001). On meta-regression, medialized RSA design was associated with a 73% lower odds of GT healing (odds ratio = 0.27, 95% confidence interval = 0.11-0.68, p = 0.007) independent of mean follow-up and age at surgery. Conclusion: Lateralized RSA implants conferred no significant functional benefit over medialized implants when used in patients with PHFs. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Inflammatory bowel disease (IBD) predisposes individuals to frailty, linked with adverse outcomes. While the Fried Frailty Index (FFI) is a well-established phenotypic tool to assess frailty, its administration is cumbersome. The FRAIL scale, simpler but not widely used in IBD patients, presents an alternative. We aimed to assess the prevalence of frailty and compare the FRAIL scale with the FFI. Methods Two hundred and nine confirmed IBD patients underwent assessment using both the FFI and the FRAIL scale. Patients were categorized as non-frail, pre-frail, or frail. Pearson coefficients evaluated correlation, and unadjusted analyses assessed frailty risk factors. ROC curve analysis evaluated the FRAIL scale. Results Among participants (53.5% female, median age 44), 37% were non-frail, 50% pre-frail, and 13% frail. The FRAIL scale exhibited strong correlation with the FFI for all three categories. Age showed no significant association with frailty. Frail individuals displayed higher inflammatory markers and more severe clinical disease, with frailty more prevalent in UC than CD patients. Frail individuals also exhibited lower hemoglobin, creatinine, and albumin levels. Conclusion Frailty and pre-frailty are prevalent in the IBD population, not necessarily linked with older age. The FRAIL scale demonstrated excellent correlation with the FFI, offering a practical tool for identifying frailty in IBD without physical measurements. Future studies should explore multivariable models incorporating frailty risk factors and interventions to mitigate adverse outcomes in the IBD population.