Symptomatic Endpoints Research Articles

Evaluation of LYR-220 Mometasone Sinonasal Implants in Patients With Chronic Rhinosinusitis and Prior Ethmoid Surgery: Results From the Randomized, Blinded, Controlled BEACON Phase 2 Study.

Endoscopic sinus surgery (ESS) often fails to directly manage the underlying inflammation in chronic rhinosinusitis (CRS), resulting in symptom recurrence in a significant number of patients. LYR-220 is a long-acting (24-week) corticosteroid sinonasal implant being developed for treatment of these patients. Forty-two adults with CRS and prior ESS were enrolled in the multicenter, randomized, controlled Phase 2 (BEACON) study. Patients received LYR-220 or a sham procedure bilaterally. The primary endpoint was occurrence of any treatment-related serious adverse events (SAEs). Efficacy endpoints included change from baseline (CFBL) in Sino-Nasal Outcome Test (SNOT-22); three cardinal symptoms (3CS) of CRS (nasal blockage, nasal discharge, and facial pain/pressure); loss-of-smell; ethmoid percent opacification volume; and need for rescue treatment (systemic corticosteroids [SCS] or sinonasal surgery). No SAEs were reported in the study. SNOT-22 scores significantly improved with LYR-220versus sham from week 2 onwards, with a between group difference of -16.8 at Week 24 (p = 0.007). Between group difference at Week 24 for 3CS was -1.50 (p = 0.02) and for ethmoid percent opacification volume was -8.14 (p = 0.035). Five patients from LYR-220 group and seven from sham group used SCS. LYR-220 showed improvement versus sham in the loss-of-smell from Week 8 through the end of treatment at 24 weeks (-0.87, p = 0.026). The BEACON study demonstrated safety, efficacy, feasibility, and tolerability of LYR-220 in patients with CRS who have had prior ESS. The primary endpoint was met, with no SAEs reported. LYR-220 demonstrated statistically significant, clinically relevant improvements in key symptomatic and objective efficacy endpoints.

Dupilumab is efficacious for eosinophilic esophagitis irrespective of prior swallowed budesonide or fluticasone, or prior treatments used alongside swallowed topical corticosteroids: results from the phase 3, randomized, placebo-controlled, LIBERTY EoE TREET trial

ABSTRACT Background Standard treatments for eosinophilic esophagitis (EoE) may present adherence, tolerance, and efficacy challenges. Dupilumab 300 mg weekly is approved for the treatment of EoE in patients ≥ 1 year old, weighing ≥ 15 kg. This analysis aimed to evaluate dupilumab efficacy in patients from the LIBERTY EoE TREET trial (NCT03633617), with prior history of different EoE interventions. Research design and methods This analysis included patients from Parts B/B – C of LIBERTY EoE TREET. Dupilumab efficacy was analyzed according to prior swallowed budesonide or fluticasone use and in those patients with previously trialed food elimination diet, esophageal dilation, or baseline proton pump inhibitor use, as stratified by prior swallowed topical corticosteroid (STC) use or STC inadequate response/intolerance/contraindication. Results Dupilumab improved the proportion of patients achieving peak intraepithelial eosinophil count ≤ 6 eosinophils/high-power field, absolute change in Dysphagia Symptom Questionnaire score, and other histologic, symptomatic, and endoscopic endpoints vs. placebo at Week (W) 24, irrespective of prior swallowed budesonide/fluticasone use. Improvements were maintained at W52. Similar results were observed across the other subgroups. Conclusion Dupilumab was efficacious in patients with EoE irrespective of prior treatments/interventions. Clinical trial registration www.clinicaltrials.gov identifier is NCT03633617.

P0756 Etrasimod efficacy in patients with mildly to moderately active Ulcerative Colitis (modified Mayo score 4–6) in the phase 3 ELEVATE UC clinical programme

Abstract Background There is an unmet need for novel advanced therapies for patients with mildly to moderately active ulcerative colitis (UC), who are most frequently treated with aminosalicylates, steroids and thiopurines. Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post hoc analysis evaluated the efficacy and safety of etrasimod 2 mg QD vs placebo in a subpopulation of patients from the ELEVATE UC clinical programme with mildly to moderately active UC at baseline, defined as a modified Mayo score (MMS) of 4–6. Methods Data were pooled from the phase 3, randomised, global ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials, and the ELEVATE UC 40 JAPAN (NCT04706793) trial.1,2 This analysis included a subset of the pooled patient population aged ≥18 years who had a baseline MMS of 4–6, including a centrally read endoscopic subscore ≥2 and a rectal bleeding subscore (RBS) ≥1. Efficacy endpoints at Week 12 and Week 52 included clinical remission, endoscopic improvement, symptomatic remission and histologic endoscopic mucosal improvement; at Week 52, sustained clinical remission and corticosteroid (CS)-free clinical remission were assessed. Least squares mean change from baseline in patient-reported outcome 2 (PRO2) score (sum of RBS and stool frequency subscores) was assessed at each visit up to Week 52. Proportions of patients with treatment-emergent adverse events (TEAEs), serious TEAEs and TEAEs leading to discontinuation were assessed. Results In this subgroup analysis, 221 received etrasimod and 109 received placebo. Baseline characteristics were generally balanced between treatment groups; 95 (28.8%) patients were receiving CS at baseline and 241 (73.0%) were biologic/Janus kinase inhibitor naïve. Median baseline MMS was 6.0 in both treatment groups. Significantly greater proportions of patients receiving etrasimod vs placebo achieved all efficacy endpoints at Week 12 and Week 52 (Figure). A significant decrease in PRO2 score for etrasimod vs placebo was observed as early as Week 2 and continued through to Week 32; numerically greater score decreases were observed from Week 36 to Week 52 (Table). Safety was similar between the etrasimod and placebo groups, and consistent with the overall ELEVATE UC population.1 Conclusion Etrasimod demonstrated robust efficacy in clinical, symptomatic and endoscopic endpoints and safety consistent with the overall population in patients with mildly to moderately active UC, as defined by an MMS of 4–6.

684 - Amlitelimab (an anti-OX40 ligand antibody) vs placebo in patients with moderate-to-severe atopic dermatitis: study design of phase 3 OCEANA clinical trials COAST 1/2, SHORE, AQUA, and ESTUARY

Abstract Introduction/Background Amlitelimab is a fully human, nondepleting anti-OX40 Ligand (OX40L) monoclonal antibody that blocks OX40L-OX40 interactions. In addition to an acceptable safety profile, phase 2a and 2b trials showed the clinical efficacy of amlitelimab in achieving lesional and symptomatic (pruritus) endpoints and demonstrating a continued durable response when patients with moderate-to-severe atopic dermatitis (AD) were withdrawn from amlitelimab during a 28-week period, suggesting the viability of extended interval dosing (every 12 weeks [Q12W]). Objectives Phase 3 clinical trials will determine the efficacy and safety of amlitelimab every four weeks (Q4W) and Q12W dosing in patients with moderate-to-severe AD with various treatment histories. Methods OCEANA phase 3 clinical trials (COAST 1, COAST 2, SHORE, AQUA, and ESTUARY) are multinational, multicenter, randomized, double-blind, parallel group, placebo-controlled trials evaluating efficacy and safety of subcutaneous amlitelimab with two different dosing regimens. Key inclusion criteria for COAST 1/2, SHORE, and AQUA include: adults and adolescents (≥12 years old) having AD ≥1 year with inadequate response to topical treatments (within 6 months before screening) and/or systemic treatment (within 12 months before screening), validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) baseline score of 3 or 4, Eczema Area and Severity Index (EASI) baseline score of ≥16, AD involvement of ≥10% of body surface area at baseline, and weekly average Peak Pruritus Numerical Rating Scale score of ≥4. COAST 1/2 are 24-week monotherapy studies, while SHORE is a 24-week study with background topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). AQUA is a 36-week study with background TCSs and TCIs that exclusively includes participants with an inadequate response to prior treatment with AD biologics or oral Janus kinase inhibitors. Primary endpoints for COAST 1/2, SHORE, and AQUA include vIGA-AD 0/1 and a reduction from baseline of ≥2 points (for US and US reference countries) and vIGA-AD 0/1 and EASI-75 (for Japan, EU, and EU reference countries). Adult patients ≥40 kg will be randomized to amlitelimab 250 mg Q4W + 500 mg loading dose (LD), amlitelimab 250 mg Q12W + 500 mg LD, or placebo; dose will be adjusted for patients <40 kg. Trials have a 2- to 4-week screening period. Primary endpoints will be evaluated at Week 24 for COAST 1/2 and SHORE and at Week 36 for AQUA, with expected enrollment of 420, 420, 496, and 249 patients in each study, respectively. Patients who have completed COAST 1/2 or SHORE can elect to enter the ESTUARY blinded extension study; patients completing AQUA can enter RIVER-AD, an open-label long-term study. Upon entering ESTUARY, clinical responders previously on 250 mg Q4W +LD will be randomized to 250 mg Q4W, 250 mg Q12W, or treatment withdrawal (placebo), while nonresponders will continue on 250 mg Q4W. Clinical responders previously on 250 mg Q12W +LD will be randomized to 250 mg Q12W or treatment withdrawal (placebo), while nonresponders will be randomized to 250 mg Q12W or 250 mg Q4W. Clinical responders previously on placebo will continue placebo, while nonresponders on placebo will receive amlitelimab 250 mg Q4W +LD. Participants not entering the ESTUARY or RIVER-AD trials will be included in a 16-week safety follow-up. ESTUARY and RIVER-AD will evaluate long-term safety and efficacy. Biopsies and blood samples will be collected at various timepoints in the OCEANA phase 3 trials. Results Enrollment for the OCEANA phase 3 trials began Q4 2023. COAST 1/2, SHORE, and AQUA trials are expected to be completed in 2026. Conclusions Results of the clinical trials should provide further evidence demonstrating the efficacy and safety of amlitelimab in treating moderate-to-severe AD using two different dosing regimens, including an extended dosing regimen, in patients with various treatment histories.

Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Programme.

Ulcerative colitis [UC], a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency [SF], rectal bleeding [RB], bowel urgency [BU], abdominal pain [AP], and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, 'comprehensive symptom control', defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at Week 4. The results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo [PBO] and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis. By Week [W] 2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52. Mirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks [NCT03518086; NCT03524092].

AERIFY-1/2: two phase 3, randomised, controlled trials of itepekimab in former smokers with moderate-to-severe COPD

BackgroundAccumulating data implicate interleukin (IL)-33, a proinflammatory cytokine released locally upon epithelial cell damage, in the pathogenesis of COPD. In a phase 2 study, itepekimab, a human monoclonal antibody against IL-33, reduced exacerbations and improved lung function in a subgroup analysis of former smokers with COPD with an acceptable safety profile.MethodsThe study designs of AERIFY-1 and AERIFY-2 are described in this article.DiscussionThe primary objective of AERIFY-1/2 (NCT04701983/NCT04751487), two phase 3 randomised, double-blind, placebo-controlled trials, is to assess the efficacy and safety of itepekimabversusplacebo in a population of former smokers with moderate-to-severe COPD over up to 52 weeks. An additional secondary population of current smokers are being enrolled in AERIFY-2. These two studies will enrol patients (aged 40–85 years) with COPD and chronic bronchitis who had ≥2 moderate or ≥ 1 severe exacerbations within the previous year despite standard-of-care triple or double background therapy. All participants are required to have ≥10-pack-year smoking history, and ≥6 months since smoking cessation for former smokers. The primary end-point is the annualised rate of moderate or severe acute exacerbation of COPD. Secondary end-points include change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 s, and annualised frequency of severe exacerbations. Symptomatic end-points include Evaluating Respiratory Symptoms in COPD and St. George's Respiratory Questionnaire, safety and anti-drug antibody responses.

COVID-19 Vaccine Efficacy in Participants With Weakened Immune Systems From 4 Randomized Controlled Trials.

Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods. A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus. For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials.

P568 Clinical relevance of baseline and change in Urgency Numeric Rating Scale score for mirikizumab treatment for Ulcerative Colitis

Abstract Background Mirikizumab (MIRI), an anti-IL-23p19 antibody, has demonstrated efficacy/safety in moderately-to-severely active ulcerative colitis (UC) Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092). This analysis evaluated induction and maintenance efficacy of MIRI among patients with different baseline (BL) bowel urgency severity. Methods In LUCENT-1, patients were randomized to receive 3 intravenous doses of 300mg MIRI or placebo (PBO); 1 every 4 weeks (Q4W). In LUCENT-2, responders to MIRI induction at W12 were rerandomized to subcutaneous 200mg MIRI or PBO Q4W through W40 (52W continuous treatment). Endpoints: clinical response, clinical remission, endoscopic remission, symptomatic remission at W12 and W52 (definitions in figure legend), Urgency Numeric Rating Scale ([UNRS]: 11-point scale from 0 [no urgency] to 10 [worst possible urgency]). Analysis: Fisher's exact test with non-responder imputation by patient induction BL UNRS score: 0-3, 4-6, and 7-10; score cut-offs based on ≥3 being a clinically meaningful improvement (JPRO 2022;6:114). Results Number of patients by BL UNRS score of 0-3, 4-6, or 7-10: W12 – 149, 437, 576 patients, respectively; W52 – 70, 215, 259 MIRI responders. At W12 and W52, a significantly greater proportion of MIRI-treated patients achieved clinical response, clinical remission, endoscopic remission, and symptomatic remission, regardless of UNRS score group at induction BL, for all comparisons except W52 clinical remission score 0-3 (Figure 1). In general, across clinical endpoints and regardless of BL UNRS score, MIRI treatment improved UNRS scores at W12 and W52 for a majority of patients, regardless of achievement of the clinical endpoint, although to a lesser extent when not achieved. MIRI treatment improved UNRS scores at W12 and W52 to a greater extent than PBO treatment regardless of achievement of clinical endpoint (Table 1; clinical remission data shown). Regardless of BL UNRS score, individual-point score shift data (not shown) illustrated that score shifts generally were distributed across lower scores at W12 and W52 than BL. This is relevant since Dubinsky and colleagues (JPRO 2022;6:31) demonstrated that a UNRS 1-2-point change in score can be important to a patient. Conclusion Regardless of BL bowel urgency severity based on UNRS score, MIRI is efficacious in achieving symptomatic, endoscopic, and clinical endpoints in UC patients. MIRI improves bowel urgency severity vs PBO even if clinical endpoints are not achieved. Observing shifts in UNRS scores along the UNRS scale, regardless of starting point, may aid in understanding a patient’s efficacy outcomes. These results support MIRI’s efficacy in bowel urgency and the clinical relevance of bowel urgency severity assessment over time.

Abstract WMP1: Complications Of Intravenous Tenecteplase For The Treatment Of Acute Ischemic Stroke: A Systematic Review And Meta-Analysis

Introduction: Prior systematic reviews have focused on a comparison of efficacy endpoints between tenecteplase (TNK) and alteplase. The objectives of this study are to determine whether the rate of treatment complications differs between patients treated with the two agents. Methods: This systematic review (CRD42022303835) was performed according to PRISMA guidelines. We included prospective, interventional studies and prospective and retrospective observational studies. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science and the ClinicalTrials.gov registry from inception through June 3 rd 2022. The primary endpoint was symptomatic intracranial hemorrhage (sICH) and secondary endpoints included any ICH, mortality, angioedema, gastrointestinal hemorrhage and other extracranial hemorrhage. We performed separate random effects meta analyses for each endpoint. Evidence was synthesized as relative risks, comparing subjects exposed to TNK versus alteplase as well as absolute risks in those treated with TNK. Results: Of 2,226 records identified, 26 were eligible for inclusion including 7,921 patients. Seventeen studies included alteplase as a comparator group and 10 were non-comparative. The relative risk of sICH in patients treated with TNK compared with alteplase was 0.93 (95% CI: 0.68-1.28). Across those treated with low, medium and high doses of TNK, the relative risks were 0.78 (95% CI: 0.22-2.82), 0.84 (95% CI: 0.58-1.20) and 2.31 (0.69-7.75) respectively. The unadjusted rate of sICH, including comparative and non-comparative studies, was 1%, 2% and 4% within the low, medium and high dose groups. Discussion: To-date, this is the most comprehensive systematic review examining relative complications of TNK and alteplase. The rate of treatment harms is broadly comparable between those treated with the two agents. We present evidence that the rate of sICH may be increased in those treated with higher doses of TNK.

P773 Extended induction in the True North open-label extension study: clinical outcomes of ~2 years of ozanimod treatment

Abstract Background Ozanimod is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis in adults. In the phase 3, 52-week, double-blind True North (TN) study, Week 10 clinical nonresponders to ozanimod could enter the open-label extension (OLE) to continue treatment. Previous analysis showed that approximately 50% of Week 10 nonresponders achieved symptomatic clinical response with extended induction during the OLE in as early as 5 weeks. The current analysis evaluated long-term clinical and symptomatic endpoints up to 2 years in this delayed responder subgroup. Methods Efficacy data were analysed for TN Week 10 ozanimod nonresponders who subsequently received open-label ozanimod in the OLE, both by whole subgroup and original study arms (double-blind [Cohort 1] and open-label ozanimod [Cohort 2]) (data cutoff: January 10, 2022). Endpoints included symptomatic clinical response, symptomatic clinical remission, total Mayo score, clinical response, clinical remission, and corticosteroid (CS)-free remission up to OLE Week 94 (104 weeks of continuous ozanimod treatment). Data were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 226 nonresponders at TN Week 10 entered the OLE (Cohort 1, n=150; Cohort 2, n=76). Males comprised 67% of this subgroup, and mean (SD) age was 39.6 (13.6) years. Symptomatic clinical response (Figure 1), symptomatic clinical remission, and reduction in partial Mayo scores were observed as early as OLE Week 5 and were maintained through OLE Week 94. Minimal change in total Mayo score was observed from TN Week 0 (baseline) to TN Week 10 (OLE Week 0), but significant reductions from baseline occurred by OLE Week 46 (–4.2 [2.7]) and OLE Week 94 (–5.3 [2.6]). Overall, 62% of patients achieved clinical response, 26% achieved clinical remission, and 24% achieved CS-free remission at OLE Week 46; these increased to 74%, 35%, and 33%, respectively, by OLE Week 94 in the OC analysis (Figure 2). Data were similar between Cohorts 1 and 2. Conclusion Symptomatic response in ozanimod nonresponders was observed as early as 5 weeks after extended induction with ozanimod. Delayed response to ozanimod was maintained for up to 2 years as demonstrated by both symptomatic and objective endpoints. Even in those with delayed initial response, efficacy of ozanimod was durable.

P687 Durability of recaptured response to ozanimod during the True North open-label extension

Abstract Background Ozanimod is approved in the EU, US, and other countries for treatment of moderately to severely active ulcerative colitis (UC) in adults. In the phase 3 True North (TN) study, ozanimod 0.92 mg once daily demonstrated efficacy and safety for up to 52 weeks in patients (pts) with moderately to severely active UC. This open-label extension (OLE) analysis evaluated the long-term durability of ozanimod based on symptomatic and clinical endpoints in pts who experienced disease relapse while on placebo during the TN maintenance period (MP) and then recaptured response to ozanimod during the OLE. Methods Responders to ozanimod 10-week induction therapy were rerandomised 1:1 to ozanimod (n=230) or placebo (n=227); this OLE interim analysis (data cutoff: January 10, 2022, at which point the OLE Week 94 disposition was available for pts) included all pts who relapsed on placebo during the MP and reinitiated ozanimod in the OLE. Endpoints included symptomatic response and remission, clinical response and clinical remission (which include endoscopy subscores), and corticosteroid (CS)-free remission (clinical remission while off CS for ≥12 weeks) evaluated using observed case (OC) and nonresponder imputation (NRI) analyses, and mean total Mayo score over time. Results A total of 77/227 pts (34%) rerandomised to placebo during MP experienced a relapse after a median of 12.7 weeks and all entered the OLE. Symptomatic response was achieved by 46/73 (63%) pts 5 weeks after restarting ozanimod in the OLE (NRI analysis: 60% at OLE Week 5) and in 32/33 (97%) by OLE Week 94 in the OC analysis. Symptomatic remission was also achieved by OLE Week 5 by 24/73 (33%) pts. Sustained efficacy of ozanimod reinitiation was also demonstrated comparing OLE Weeks 46 and 94 across clinical endpoints by OC analysis (clinical response, 76% and 86%; clinical remission, 44% and 59%; CS-free remission, 37% and 52%) and NRI analysis (clinical response, 42% and 31%; clinical remission, 25% and 22%; CS-free remission, 21% and 20%) (Figure 1). In addition, 56.3%, 52.6%, and 50% of pts who experienced clinical response, clinical remission, and CS-free remission, respectively, at OLE Week 46 continued to sustain these endpoints at OLE Week 94. Reductions in mean total Mayo score at OLE Week 46 were also sustained through OLE Week 94 (Figure 2). Conclusion Response to ozanimod was regained after temporary therapy discontinuation for most pts, and this response was durable for up to 2 years as demonstrated by both symptomatic and clinical endpoints in this interim analysis from the TN OLE study. These results suggest that pts who experienced disease relapse after temporarily holding ozanimod in clinical practice may benefit from resumption of ozanimod.

P609 Impact of prior biologic exposure on durability of recaptured response to ozanimod during the True North open-label extension study

Abstract Background In the phase 3 True North (TN) study, ozanimod (OZA) 0.92 mg once daily showed efficacy and safety for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis, and is approved for adults in the EU, US, and other countries for this indication. This analysis (data cutoff: 10 January 2022) evaluated the impact of prior biologic exposure on the long-term durability of response in pts who experienced disease relapse while on placebo (PBO) during the TN maintenance period (MP) and then recaptured response to OZA during the TN open-label extension (OLE). Methods Responders to OZA 10-week induction therapy who were biologic-naive or exposed to prior biologics at baseline were rerandomised 1:1 to OZA (n=230) or PBO (n=227) during the TN MP. Pts who relapsed while on PBO subsequently entered the OLE and reinitiated open-label OZA in this interim OLE analysis. Symptomatic, clinical, endoscopic, and histologic endpoints were evaluated by observed case (OC) and nonresponder imputation (NRI) analyses. Results This analysis included 38 biologic-naive and 38 biologic-exposed pts who entered the OLE after disease relapse on PBO (median time to relapse, 13.1 and 11.2 weeks, respectively). Symptomatic clinical response based on NRI was achieved by 26/38 (68.4%) of biologic-naive and 20/38 (52.6%) of biologic-exposed pts 5 weeks after restarting OZA in the OLE. Symptomatic clinical response by OC analysis at OLE Week 5 was achieved in 72.2% (26/36) and 55.6% (20/36) of biologic-naive and -exposed pts, respectively. Although a greater proportion of biologic-naive vs -exposed pts completed OLE Week 94 (65.8% vs 39.5%), OC rates of symptomatic clinical response at OLE Week 94 were similar (biologic-naive: 95.0% [19/20] vs biologic-exposed: 100.0% [13/13]). Key clinical, endoscopic, and histologic endpoints are shown in Fig 1. Durability of response between OLE Weeks 46 and 94 was similar in biologic-naive (40%–56%) vs -exposed pts (50%–67%) but varied depending on endpoints (NRI analysis). Reductions in mean [SD] total Mayo score were similar and sustained through OLE Week 94 in biologic-naive and -exposed pts (OLE Week 0: 8.9 [1.8] and 9.3 [1.6], respectively; OLE Week 46: 2.3 [1.7] and 4.2 [2.6], respectively; OLE Week 94: 2.6 [2.0] and 2.6 [1.4], respectively) (Fig 2). Conclusion In pts who lost clinical response after OZA treatment withdrawal, symptomatic clinical response was recaptured within 5 weeks of OZA reinitiation in the majority of pts, and clinical benefit was maintained for up to 94 weeks (extent of current analysis) in biologic-naive and -exposed pts. This suggests that in clinical practice, pts who experience a disease relapse after temporarily holding OZA may benefit from resumption of OZA.

P719 Symptomatic improvement and long-term stability of ulcerative colitis symptoms over 3 years of ozanimod treatment

Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod over 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). Pts completing 52 weeks of TN were eligible for the ongoing TN open-label extension (OLE) assessing the long-term efficacy and safety of ozanimod. Presented here is the interim analysis of the TN OLE focused on the symptomatic efficacy of ozanimod in pts with approximately 3 years of continuous ozanimod treatment. Methods Pts who achieved clinical response after receiving 52 weeks of continuous ozanimod during TN and subsequently entered the TN OLE were evaluated (data cutoff: 10 January 2022, at which point the OLE Week 94 disposition was available for pts). Patient-reported (rectal bleeding subscore [RBS] and stool frequency subscore [SFS]) and clinician-reported (Physician’s Global Assessment) symptomatic outcomes were determined. Symptomatic clinical response (partial Mayo score [PMS] ≥1 point and ≥30% reduction in PMS with ≥1-point decrease in RBS or absolute RBS of ≤1) and symptomatic clinical remission (RBS=0 and SFS ≤1 [and decrease of ≥1 point from baseline SFS]) were evaluated at OLE Week 5 through OLE Week 94 (146 weeks of continuous ozanimod treatment) using observed case (OC) and nonresponder imputation (NRI) analyses. PMS, RBS, and SFS were assessed from TN baseline to OLE Week 94. Results In all, 131 pts entered the OLE after achieving clinical response following 52 weeks of continuous ozanimod during TN. At data cutoff, 87.0% completed OLE Week 46 (98 weeks of continuous ozanimod) and 71.8% completed OLE Week 94 (146 weeks of continuous ozanimod). Pts had a mean age of 44 years and 52% were female. Most (68%) had left-sided UC disease, 24% had concomitant corticosteroid use at TN baseline, and 32% had prior exposure to tumor necrosis factor inhibitors. Symptomatic clinical response and symptomatic clinical remission were observed in 100.0% (Figure 1A) and 84.4% (Figure 2A) of pts, respectively, at OLE Week 5 in the OC analysis (93.1% [Figure 1B] and 78.6% [Figure 2B] in the NRI analysis). Rates of symptomatic clinical response and symptomatic clinical remission were maintained through OLE Week 94 in the OC analysis and decreased slightly over time in the NRI analysis. Reductions in mean PMS from baseline were observed during TN and sustained through OLE Week 94. Reductions from TN baseline in RBS (Figure 3) and SFS (Figure 4) were also observed through OLE Week 94. Conclusion This interim analysis of the TN OLE focusing on symptomatic endpoints found that most pts who achieved clinical response after 1 year of ozanimod sustained symptom control for another 2 years.

Transmantle and transvenous pressure gradients in cerebrospinal fluid disorders.

Hydrocephalus is the symptomatic endpoint of a variety of disease processes. Simple hydrodynamic models have failed to explain the entire spectrum of cerebrospinal fluid (CSF) disorders. Physical principles argue that for ventricles to expand, they must be driven by a force, Fishman's transmantle pressure gradient (TMPG). However, the literature to date, reviewed herein, is heterogenous and fails to consistently measure a TMPG. The venous system, like CSF, traverses the cerebral mantle, and thus analogous transparenchymal and transvenous pressure gradients have been described, reliant on the differential haemodynamics of the deep and superficial venous systems. Interpreting CSF disorders through these models provides new insights into the possible pathophysiological mechanisms underlying these diseases. However, until more sophisticated testing is performed, these models should remain heuristics.

Benefits of budesonide/glycopyrrolate/formoterol fumarate (BGF) on symptoms and quality of life in patients with COPD in the ETHOS trial

BackgroundWe report the long-term effects of triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) vs glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF) on symptoms and health-related quality of life (HRQoL) over 52 weeks in the Phase III ETHOS study of patients with moderate-to-very severe COPD. MethodsETHOS was a randomized, double-blind, multi-center, parallel-group study in symptomatic patients with COPD who experienced ≥1 moderate/severe exacerbation in the previous year. Patients received twice-daily BGF 320/18/9.6 μg, BGF 160/18/9.6 μg, GFF 18/9.6 μg, or BFF 320/9.6 μg, administered via a single Aerosphere inhaler, for 52 weeks. ResultsThe modified intent-to-treat population included 8509 patients (mean age 64.7 years; 59.7% male; mean COPD Assessment Test score, 19.6). BGF significantly reduced rescue medication use vs GFF and BFF (−0.53 puffs/day [p < 0.0001] and −0.35 puffs/day [p = 0.0002], respectively, with BGF 320 over 52 weeks). BGF 320 also significantly improved St George's Respiratory Questionnaire (SGRQ) total score over 24 and 52 weeks vs dual therapies, resulting in the greatest proportion of SGRQ responders vs dual therapies over 24 weeks (52.5% vs 42.5% [GFF] and 45.2% [BFF]) and 52 weeks (47.0% vs 37.8% [GFF] and 41.0% [BFF]). Similar results were observed with BGF 160.Benefits were also observed vs dual therapies in symptomatic endpoints including Transition Dyspnea Index focal score, EXAcerbations of Chronic pulmonary disease Tool total scores and Evaluating Respiratory Symptoms in COPD total scores over 24 and 52 weeks. ConclusionsBGF triple therapy improved symptoms and HRQoL vs dual therapies over 24 and 52 weeks in patients with moderate-to-very severe COPD.

DOP86 Corticosteroid-sparing effects of ustekinumab therapy for Ulcerative Colitis through 3 years: UNIFI long-term extension

Abstract Background Ustekinumab (UST) is an IL12/23 blocker approved for use in Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients (pts) with moderate-severe UC, &amp;gt;90% of the pts who achieved clinical response or remission at week (wk) 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid-sparing effects of UST treatment through 3 years among pts who were treated in the UNIFI long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 wks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, pts in the LTE were eligible to receive dose adjustment starting at wk56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Pts in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Efficacy was evaluated in randomized pts using symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0). During the maintenance study, all pts receiving corticosteroids at maintenance baseline were required to initiate tapering. Through wk152 of the LTE, symptomatic remission endpoints were calculated with treatment failure and missing data nonresponder imputation, and dose adjustment was not considered to be a treatment failure. Missing corticosteroid dose data was managed using last observation carried forward. Results Of the 284 pts in the randomized population who were treated with UST in the LTE, 139 were receiving corticosteroids at maintenance baseline. Of these, 91.4% (n=127) were no longer receiving corticosteroids at wk152. The average prednisone-equivalent corticosteroid dose among pts receiving corticosteroids at maintenance baseline in the q8w group was 15.4 mg/day at maintenance baseline and 1.7 mg/day at wks44 &amp; 152. In the q12w group, average prednisone-equivalent doses were 15.4, 1.0, and 4.6 mg/day, respectively (Table 1). Corticosteroid-free symptomatic remission rates through wk152 are summarized in Table 2. Results were similar for the q8w and q12w maintenance doses. Of the UST-treated pts who were in symptomatic remission at wk152, 94.6% (88/93) in the q12w group and 98.0% (97/99) in the q8w group were corticosteroid-free. Conclusion UST maintenance therapy, with both q8w and q12w dosing regimens, was effective in reducing and eliminating the use of corticosteroids in pts with UC through 3 years. Through 3 years of treatment with UST, the majority of pts in symptomatic remission were corticosteroid free.

Safety and efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy: a systematic review and meta-analysis of observational data

BackgroundAchieving the best possible reperfusion is a key determinant of clinical outcome after mechanical thrombectomy (MT). However, data on the safety and efficacy of intra-arterial (IA) fibrinolytics as an adjunct...

Dyspnea in Patients Receiving Radical Radiotherapy for Non-Small Cell Lung Cancer: A Prospective Study.

Background and PurposeDyspnea is an important symptomatic endpoint for assessment of radiation-induced lung injury (RILI) following radical radiotherapy in locally advanced disease, which remains the mainstay of treatment at the time of significant advances in therapy including combination treatments with immunotherapy and chemotherapy and the use of local ablative radiotherapy techniques. We investigated the relationship between dose-volume parameters and subjective changes in dyspnea as a measure of RILI and the relationship to spirometry.Material and MethodsEighty patients receiving radical radiotherapy for non-small cell lung cancer were prospectively assessed for dyspnea using two patient-completed tools: EORTC QLQ-LC13 dyspnea quality of life assessment and dyspnea visual analogue scale (VAS). Global quality of life, spirometry and radiation pneumonitis grade were also assessed. Comparisons were made with lung dose-volume parameters.ResultsThe median survival of the cohort was 26 months. In the evaluable group of 59 patients there were positive correlations between lung dose-volume parameters and a change in dyspnea quality of life scale at 3 months (V30 p=0.017; V40 p=0.026; V50 p=0.049; mean lung dose p=0.05), and a change in dyspnea VAS at 6 months (V30 p=0.05; V40 p=0.026; V50 p=0.028) after radiotherapy. Lung dose-volume parameters predicted a 10% increase in dyspnea quality of life score at 3 months (V40; p=0.041, V50; p=0.037) and dyspnea VAS score at 6 months (V40; p=0.027) post-treatment.ConclusionsWorsening of dyspnea is an important symptom of RILI. We demonstrate a relationship between lung dose-volume parameters and a 10% worsening of subjective dyspnea scores. Our findings support the use of subjective dyspnea tools in future studies on radiation-induced lung toxicity, particularly at doses below conventional lung radiation tolerance limits.

Symptomatic endpoint responder rates to BAROSTIM Therapy

Abstract Background Patients with heart failure with reduced ejection fraction (HFrEF) have varying responses to symptomatic endpoints with device-based HF therapies. Purpose Evaluate the symptomatic response to baroreflex activation therapy (BAT) at six months. Methods In a trial of subjects with NYHA Class II (recently III) or III HFrEF, left ventricular EF≤35%, guideline directed medical HF therapy (GDMT), no indication for cardiac resynchronization therapy, and NT-proBNP&amp;lt;1600 pg/ml, 264 subjects were randomized to BAROSTIM therapy plus GDMT (BAT group) or GDMT alone (Control group). Six-minute hall walk (6MHW), Minnesota Living with HF (QOL) and NYHA Class were analyzed. Clinically relevant responders were defined by 6-month improvement in 6MHW&amp;gt;10%, QOL&amp;gt;5 points or improvement in at least one NYHA class; super responders were defined by 6-month improvement in 6MHW&amp;gt;20%, QOL&amp;gt;10 points or improvement to NYHA class I. Results Both clinically relevant and super responders were significantly higher in BAT versus Control subjects for all symptomatic endpoints. In BAT subjects, 72% had clinically relevant improvements in ≥2 endpoints compared to 29% of Control subjects (p&amp;lt;0.001), and 28% of BAT subjects had super responder improvements in ≥2 endpoints versus 10% of Control subjects (p&amp;lt;0.001). Conclusion Among subjects with symptomatic HFrEF, treatment with BAT resulted in clinically relevant and super responder rates. The BAT clinically relevant and super responder rates are similar to those seen with CRT, in CRT-indicated patients. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): CVRx, Inc.

Nopal fiber (Opuntia ficus-indica) improves symptoms in irritable bowel syndrome in the short term: a randomized controlled trial.

Clinical guidelines provide limited and conflicting recommendations regarding dietary fiber supplementation in irritable bowel syndrome (IBS). Nopal (Opuntia ficus-indica) is a cactus plant fiber containing both insoluble and soluble fibers that may have therapeutic potential in IBS. Our aim was to evaluate the dose-response effect of extracted nopal fiber powder on symptoms in IBS. We performed a 4-arm, double-blind, parallel, randomized controlled trial in 60 patients fulfilling Rome IV criteria for IBS. Patients were randomized and blindly allocated to receive either nopal fiber (10, 20, or 30g/day) or placebo (30g/day dextrose) for one week and to keep their usual diet. Symptom severity (Global Symptom Question, IBS-SSS, Gastrointestinal Symptom Rating Scale), stool frequency and consistency (Bristol Stool Form Scale), breath hydrogen response, and stool short-chain fatty acids (SCFA) were measured at baseline and follow-up. Significantly more patients reported adequate relief of symptoms after 20g/day (87%, p=0.008) and 30g/day (80%, p=0.025) of nopal fiber compared to placebo (33%). More patients receiving 20g/day nopal fiber (67%) had a>50% reduction in IBS-SSS compared to placebo (20%, p=0.027), whereas the 30g/day dose induced more loose stools (p=0.027). Response rates were similar among IBS subtypes. There were no differences in breath hydrogen or stool SCFA between groups. Nopal fiber supplementation at doses of 20 and 30g/day was associated with short-term improvement in IBS symptoms, warranting a fully powered clinical trial of longer duration with symptomatic, physiological, and microbiological endpoints.